Philip King - Academia.edu (original) (raw)

Papers by Philip King

Encyclopedia of Signaling Molecules, 2018

JCI Insight, 2022

Capillary malformation-arteriovenous malformation (CM-AVM) is a blood vascular anomaly caused by ... more Capillary malformation-arteriovenous malformation (CM-AVM) is a blood vascular anomaly caused by inherited loss of function mutations in RASA1 or EPHB4 genes that encode p120 Ras GTPase-activating protein (p120 RasGAP/RASA1) and Ephrin receptor B4 (EPHB4) respectively. However, whether RASA1 and EPHB4 function in the same molecular signaling pathway to regulate the blood vasculature is uncertain. Here, we show that induced endothelial cell (EC)-specific disruption of Ephb4 in mice results in accumulation of collagen IV in the EC endoplasmic reticulum leading to EC apoptotic death and defective developmental, neonatal and pathological angiogenesis, as reported previously in induced EC-specific RASA1-deficient mice. Moreover, defects in angiogenic responses in EPHB4-deficient mice can be rescued by drugs that inhibit signaling through the Ras pathway and drugs that promote collagen IV export from the ER. However, EPHB4 mutant mice that express a form of EPHB4 that is unable to physically engage RASA1 but retains protein tyrosine kinase activity show normal angiogenic responses. These findings provide strong evidence that RASA1 and EPHB4 function in the same signaling pathway to protect against the development of CM-AVM independent of physical interaction and have important implications with regards possible means of treatment of this disease.

Methods in Molecular Biology, 2021

There is increasing interest in the study of the mammalian lymphatic system, including the lympha... more There is increasing interest in the study of the mammalian lymphatic system, including the lymphatic endothelial cells (LECs) that make up lymphatic vessels. The ability to isolate primary LECs from tissue of normal and genetically modified mice permits detailed analysis of this unique cell type. Here, we describe a robust protocol for the isolation and in vitro expansion of LECs from mouse lung by antibody-based magnetic separation.

Cell Communication and Signaling, 2021

Once thought of primarily as a means to neutralize pathogens or to facilitate feeding, endocytosi... more Once thought of primarily as a means to neutralize pathogens or to facilitate feeding, endocytosis is now known to regulate a wide range of eukaryotic cell processes. Among these are regulation of signal transduction, mitosis, lipid homeostasis, and directed migration, among others. Less well-appreciated are the roles various forms of endocytosis plays in regulating αβ and, especially, γδ T cell functions, such as T cell receptor signaling, antigen discovery by trogocytosis, and activated cell growth. Herein we examine the contribution of both clathrin-mediated and clathrin-independent mechanisms of endocytosis to T cell biology.

RASA1, a negative regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway,... more RASA1, a negative regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway, is essential for the development and maintenance of lymphatic vessel (LV) valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study we show that induced endothelial cell (EC)-specific disruption of Rasa1 in mid-gestation mouse embryos did not affect initial specification of LVV or central VV but did affect their continued development. Similarly, switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV in RASA1-deficient embryos was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming EC and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasa1 in adult mice resulted in venous hypertension and impaired VV fu...

Nature Communications, 2020

Macropinocytosis is an evolutionarily-conserved, large-scale, fluid-phase form of endocytosis tha... more Macropinocytosis is an evolutionarily-conserved, large-scale, fluid-phase form of endocytosis that has been ascribed different functions including antigen presentation in macrophages and dendritic cells, regulation of receptor density in neurons, and regulation of tumor growth under nutrient-limiting conditions. However, whether macropinocytosis regulates the expansion of non-transformed mammalian cells is unknown. Here we show that primary mouse and human T cells engage in macropinocytosis that increases in magnitude upon T cell activation to support T cell growth even under amino acid (AA) replete conditions. Mechanistically, macropinocytosis in T cells provides access of extracellular AA to an endolysosomal compartment to sustain activation of the mechanistic target of rapamycin complex 1 (mTORC1) that promotes T cell growth. Our results thus implicate a function of macropinocytosis in mammalian cell growth beyond Ras-transformed tumor cells via sustained mTORC1 activation.

Journal of Clinical Investigation, 2019

Loss of RASA1 in these EC would be expected to result in dysregulated Ras signal transduction tha... more Loss of RASA1 in these EC would be expected to result in dysregulated Ras signal transduction that could drive lesion development. Recently, it has been shown that inactivating germline mutations of EPHB4, which encodes the ephrin receptor B4, are responsible for the majority of CM-AVM cases that are not explained by RASA1 mutation (12). Accordingly, CM-AVM resulting from RASA1 mutation has been renamed CM-AVM1 and CM-AVM resulting from EPHB4 mutation has been named CM-AVM2. Clinically, CM-AVM1 and CM-AVM2 are almost indistinguishable except for the additional occurrence of telangiectasias in CM-AVM2 (12). These findings raise the possibility that lesion development in CM-AVM results from loss of an EPHB4-RASA1 negative-regulatory axis in EC in which EPHB4 serves to recruit RASA1 to the inner leaflet of the cell membrane allowing its juxtaposition to Ras-GTP (12, 13). It is likely that second hit mutations of EPHB4 are required for the development of lesions in CM-AVM2, although this has yet to be demonstrated. Studies of genetically engineered mutant mice have the potential to provide information upon the pathogenesis of diseases such as CM-AVM that could not otherwise be obtained from human studies alone. Concerning RASA1 and CM-AVM1, constitutive loss of Rasa1 in mice results in mid-gestation lethality at E10.5 as a consequence of impaired vascular development (14, 15). Developmental angiogenesis, in which primitive vascular plexuses are remodeled into hierarchical vascular networks, is abnormal in these embryos. This is evident in the yolk sac for example where EC initially assemble into a vascular plexus but then fail to organize into a vascular network that supplies blood to the

European journal of medical genetics, 2018

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular diso... more Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular disorder that is associated with inherited inactivating mutations of the RASA1 gene in the majority of cases. Characteristically, patients exhibit one or more focal cutaneous CM that may occur alone or together with AVM, arteriovenous fistulas or lymphatic vessel abnormalities. The focal nature and varying presentation of lesions has led to the hypothesis that somatic "second hit" inactivating mutations of RASA1 are necessary for disease development. In this study, we examined CM from four different CM-AVM patients for the presence of somatically acquired RASA1 mutations. All four patients were shown to possess inactivating heterozygous germline RASA1 mutations. In one of the patients, a somatic inactivating RASA1 mutation (c.1534C > T, p.Arg512*) was additionally identified in CM lesion tissue. The somatic RASA1 mutation was detected within endothelial cells specifically and wa...

The Journal of clinical investigation, Jan 22, 2017

Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) d... more Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) disorder that is caused by inherited inactivating mutations of the RASA1 gene, which encodes p120 RasGAP (RASA1), a negative regulator of the Ras small GTP-binding protein. How RASA1 mutations lead to the LV leakage defects that occur in CM-AVM is not understood. Here, we report that disruption of the Rasa1 gene in adult mice resulted in loss of LV endothelial cells (LECs) specifically from the leaflets of intraluminal valves in collecting LVs. As a result, valves were unable to prevent fluid backflow and the vessels were ineffective pumps. Furthermore, disruption of Rasa1 in midgestation resulted in LEC apoptosis in developing LV valves and consequently failed LV valvulogenesis. Similar phenotypes were observed in induced RASA1-deficient adult mice and embryos expressing a catalytically inactive RASA1R780Q mutation. Thus, RASA1 catalytic activity is essential for the function and develop...

American Journal of Clinical and Experimental Immunology, 2012

T cell receptor-induced activation of the Ras signaling pathway is essential for T cell developme... more T cell receptor-induced activation of the Ras signaling pathway is essential for T cell development, proliferation and differentiation. Given the central role of Ras in T cell biology its activation must be tightly regulated. However, precisely how Ras activation is controlled in T cells is not completely understood. In this review, we provide a summary of the known factors and mechanisms involved in positive and negative regulation of Ras activation in the T cell lineage.

Advances in Experimental Medicine and Biology, 1993

Dendritic cells (DC) are identified both by morphology and function (1-3). These cells are locali... more Dendritic cells (DC) are identified both by morphology and function (1-3). These cells are localised to T cell micro-environments and are the most potent known accessory inducer cells for T cell responses. Even when there is heterogeneity in in vitro comparative accessory cell function (i. e. when more than one cell type can present), then the DC almost invariably prove to be the most potent relative inducers (4, 5). Thus the distinguishing molecular mechanisms involved in DC — T cell interaction that might account for this distinctive inducer capacity is obviously of considerable interest.

Encyclopedia of Signaling Molecules, 2012

The American journal of pathology, 2014

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascula... more Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascular (BV) disorder characterized by CM and fast flow BV lesions. Inactivating mutations of the RASA1 gene are the cause of CM-AVM in most cases. RASA1 is a GTPase-activating protein that acts as a negative regulator of the Ras small GTP-binding protein. In addition, RASA1 performs Ras-independent functions in intracellular signal transduction. Whether CM-AVM results from loss of an ability of RASA1 to regulate Ras or loss of a Ras-independent function of RASA1 is unknown. To address this, we generated Rasa1 knockin mice with an R780Q point mutation that abrogates RASA1 catalytic activity specifically. Homozygous Rasa1(R780Q/R780Q) mice showed the same severe BV abnormalities as Rasa1-null mice and died midgestation. This finding indicates that BV abnormalities in CM-AVM develop as a result of loss of an ability of RASA1 to control Ras activation and not loss of a Ras-independent function of...

Trends in cardiovascular medicine, 2014

A number of genetic diseases in man have been described in which abnormalities in the development... more A number of genetic diseases in man have been described in which abnormalities in the development and function of the lymphatic vascular (LV) system are prominent features. The genes that are mutated in these diseases are varied and include genes that encode lymphatic endothelial cell (LEC) growth factor receptors and their ligands and transcription factors that control LEC fate and function. In addition, an increasing number of genes have been identified that encode components of the Ras signal transduction pathway that conveys signals from cell surface receptors to regulate cell growth, proliferation, and differentiation. Gene targeting studies performed in mice have confirmed that the LV system is particularly susceptible to perturbations in the Ras pathway.

Current opinion in investigational drugs (London, England : 2000), 2004

Systemic lupus erythematosus (SLE) is a prevalent, non-organ-specific autoimmune disease that is ... more Systemic lupus erythematosus (SLE) is a prevalent, non-organ-specific autoimmune disease that is partially caused by genetic factors. Types of genetic factors that can contribute to lupus have been revealed by studies of naturally occurring and genetically engineered mutant mice which are susceptible to this disease. Notably, a number of mutant mice have been reported that point to defective T-lymphocyte signal transduction as one potential cause of lupus. Deficient expression of adapter proteins, cell cycle control proteins, ubiquitin ligases and transcription factors, and impaired phosphatidylinositol 3-kinase (PI3-kinase) and Ras signaling in T-cells, all promote lupus in mice. These findings have important implications for the causes and treatment of human SLE.

Encyclopedia of Signaling Molecules, 2012

Disease models & mechanisms, 2011

SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for s... more SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for signal transduction by multiple different cell surface receptors. Humans with germline SHP-2 mutations develop Noonan syndrome or LEOPARD syndrome, which are characterized by cardiovascular, neurological and skeletal abnormalities. To study how SHP-2 regulates tissue homeostasis in normal adults, we used a conditional SHP-2 mouse mutant in which loss of expression of SHP-2 was induced in multiple tissues in response to drug administration. Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality. Most strikingly, induced SHP-2-deficient mice developed severe skeletal abnormalities, including kyphoses and scolioses of the spine. Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass. Osteoclasts were essentially absent from the bones of SHP-2-deficient mice, thus accounting for the osteopetrotic phen...

Bone, 2014

Src homology-2 protein tyrosine phosphatase (SHP-2) that is encoded by the PTPN11 gene in humans ... more Src homology-2 protein tyrosine phosphatase (SHP-2) that is encoded by the PTPN11 gene in humans is an intracellular signaling molecule that couples growth factor receptors to activation of the Ras small GTP-binding protein that regulates cell growth, proliferation and differentiation. Germline mutations of PTPN11 are causative of Noonan syndrome and LEOPARD syndrome in humans in which there are recognized skeletal abnormalities that include growth retardation, spinal curvature and chest malformations. In addition, combined somatic and germline PTPN11 mutations have been shown to be responsible for a rare benign bone cartilaginous tumor disease known as metachondromatosis. In parallel, gene targeting studies performed in mice have revealed an essential role for SHP-2 as a regulator of bone and skeletal development. In this review the significance of these findings in mice to the understanding of the pathogenesis of skeletal abnormalities in humans with SHP-2 mutations is discussed.

Advances in Experimental Medicine and Biology

... J. Drappa, LA Kamen, E. Chan, M. Georgiev, D. Ashany, F. Marti, and PD King, Impaired T cell ... more ... J. Drappa, LA Kamen, E. Chan, M. Georgiev, D. Ashany, F. Marti, and PD King, Impaired T cell death and lupus-like autoimmunity in T cell ... KZ Dai, HF Harbo, EG Celius, A. Oturai, PS Sorensen, LP Ryder, P. Datta, A. Svejgaard, J. Hillert, S. Fredrikson, M. Sandberg-Wollheim, M ...

Encyclopedia of Signaling Molecules, 2018

JCI Insight, 2022

Capillary malformation-arteriovenous malformation (CM-AVM) is a blood vascular anomaly caused by ... more Capillary malformation-arteriovenous malformation (CM-AVM) is a blood vascular anomaly caused by inherited loss of function mutations in RASA1 or EPHB4 genes that encode p120 Ras GTPase-activating protein (p120 RasGAP/RASA1) and Ephrin receptor B4 (EPHB4) respectively. However, whether RASA1 and EPHB4 function in the same molecular signaling pathway to regulate the blood vasculature is uncertain. Here, we show that induced endothelial cell (EC)-specific disruption of Ephb4 in mice results in accumulation of collagen IV in the EC endoplasmic reticulum leading to EC apoptotic death and defective developmental, neonatal and pathological angiogenesis, as reported previously in induced EC-specific RASA1-deficient mice. Moreover, defects in angiogenic responses in EPHB4-deficient mice can be rescued by drugs that inhibit signaling through the Ras pathway and drugs that promote collagen IV export from the ER. However, EPHB4 mutant mice that express a form of EPHB4 that is unable to physically engage RASA1 but retains protein tyrosine kinase activity show normal angiogenic responses. These findings provide strong evidence that RASA1 and EPHB4 function in the same signaling pathway to protect against the development of CM-AVM independent of physical interaction and have important implications with regards possible means of treatment of this disease.

Methods in Molecular Biology, 2021

There is increasing interest in the study of the mammalian lymphatic system, including the lympha... more There is increasing interest in the study of the mammalian lymphatic system, including the lymphatic endothelial cells (LECs) that make up lymphatic vessels. The ability to isolate primary LECs from tissue of normal and genetically modified mice permits detailed analysis of this unique cell type. Here, we describe a robust protocol for the isolation and in vitro expansion of LECs from mouse lung by antibody-based magnetic separation.

Cell Communication and Signaling, 2021

Once thought of primarily as a means to neutralize pathogens or to facilitate feeding, endocytosi... more Once thought of primarily as a means to neutralize pathogens or to facilitate feeding, endocytosis is now known to regulate a wide range of eukaryotic cell processes. Among these are regulation of signal transduction, mitosis, lipid homeostasis, and directed migration, among others. Less well-appreciated are the roles various forms of endocytosis plays in regulating αβ and, especially, γδ T cell functions, such as T cell receptor signaling, antigen discovery by trogocytosis, and activated cell growth. Herein we examine the contribution of both clathrin-mediated and clathrin-independent mechanisms of endocytosis to T cell biology.

RASA1, a negative regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway,... more RASA1, a negative regulator of the Ras-mitogen-activated protein kinase (MAPK) signaling pathway, is essential for the development and maintenance of lymphatic vessel (LV) valves. However, whether RASA1 is required for the development and maintenance of lymphovenous valves (LVV) and venous valves (VV) is unknown. In this study we show that induced endothelial cell (EC)-specific disruption of Rasa1 in mid-gestation mouse embryos did not affect initial specification of LVV or central VV but did affect their continued development. Similarly, switch to expression of a catalytically inactive form of RASA1 resulted in impaired LVV and VV development. Blocked development of LVV in RASA1-deficient embryos was associated with accumulation of the basement membrane protein, collagen IV, in LVV-forming EC and could be partially or completely rescued by MAPK inhibitors and drugs that promote collagen IV folding. Disruption of Rasa1 in adult mice resulted in venous hypertension and impaired VV fu...

Nature Communications, 2020

Macropinocytosis is an evolutionarily-conserved, large-scale, fluid-phase form of endocytosis tha... more Macropinocytosis is an evolutionarily-conserved, large-scale, fluid-phase form of endocytosis that has been ascribed different functions including antigen presentation in macrophages and dendritic cells, regulation of receptor density in neurons, and regulation of tumor growth under nutrient-limiting conditions. However, whether macropinocytosis regulates the expansion of non-transformed mammalian cells is unknown. Here we show that primary mouse and human T cells engage in macropinocytosis that increases in magnitude upon T cell activation to support T cell growth even under amino acid (AA) replete conditions. Mechanistically, macropinocytosis in T cells provides access of extracellular AA to an endolysosomal compartment to sustain activation of the mechanistic target of rapamycin complex 1 (mTORC1) that promotes T cell growth. Our results thus implicate a function of macropinocytosis in mammalian cell growth beyond Ras-transformed tumor cells via sustained mTORC1 activation.

Journal of Clinical Investigation, 2019

Loss of RASA1 in these EC would be expected to result in dysregulated Ras signal transduction tha... more Loss of RASA1 in these EC would be expected to result in dysregulated Ras signal transduction that could drive lesion development. Recently, it has been shown that inactivating germline mutations of EPHB4, which encodes the ephrin receptor B4, are responsible for the majority of CM-AVM cases that are not explained by RASA1 mutation (12). Accordingly, CM-AVM resulting from RASA1 mutation has been renamed CM-AVM1 and CM-AVM resulting from EPHB4 mutation has been named CM-AVM2. Clinically, CM-AVM1 and CM-AVM2 are almost indistinguishable except for the additional occurrence of telangiectasias in CM-AVM2 (12). These findings raise the possibility that lesion development in CM-AVM results from loss of an EPHB4-RASA1 negative-regulatory axis in EC in which EPHB4 serves to recruit RASA1 to the inner leaflet of the cell membrane allowing its juxtaposition to Ras-GTP (12, 13). It is likely that second hit mutations of EPHB4 are required for the development of lesions in CM-AVM2, although this has yet to be demonstrated. Studies of genetically engineered mutant mice have the potential to provide information upon the pathogenesis of diseases such as CM-AVM that could not otherwise be obtained from human studies alone. Concerning RASA1 and CM-AVM1, constitutive loss of Rasa1 in mice results in mid-gestation lethality at E10.5 as a consequence of impaired vascular development (14, 15). Developmental angiogenesis, in which primitive vascular plexuses are remodeled into hierarchical vascular networks, is abnormal in these embryos. This is evident in the yolk sac for example where EC initially assemble into a vascular plexus but then fail to organize into a vascular network that supplies blood to the

European journal of medical genetics, 2018

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular diso... more Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular disorder that is associated with inherited inactivating mutations of the RASA1 gene in the majority of cases. Characteristically, patients exhibit one or more focal cutaneous CM that may occur alone or together with AVM, arteriovenous fistulas or lymphatic vessel abnormalities. The focal nature and varying presentation of lesions has led to the hypothesis that somatic "second hit" inactivating mutations of RASA1 are necessary for disease development. In this study, we examined CM from four different CM-AVM patients for the presence of somatically acquired RASA1 mutations. All four patients were shown to possess inactivating heterozygous germline RASA1 mutations. In one of the patients, a somatic inactivating RASA1 mutation (c.1534C > T, p.Arg512*) was additionally identified in CM lesion tissue. The somatic RASA1 mutation was detected within endothelial cells specifically and wa...

The Journal of clinical investigation, Jan 22, 2017

Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) d... more Capillary malformation-arteriovenous malformation (CM-AVM) is a blood and lymphatic vessel (LV) disorder that is caused by inherited inactivating mutations of the RASA1 gene, which encodes p120 RasGAP (RASA1), a negative regulator of the Ras small GTP-binding protein. How RASA1 mutations lead to the LV leakage defects that occur in CM-AVM is not understood. Here, we report that disruption of the Rasa1 gene in adult mice resulted in loss of LV endothelial cells (LECs) specifically from the leaflets of intraluminal valves in collecting LVs. As a result, valves were unable to prevent fluid backflow and the vessels were ineffective pumps. Furthermore, disruption of Rasa1 in midgestation resulted in LEC apoptosis in developing LV valves and consequently failed LV valvulogenesis. Similar phenotypes were observed in induced RASA1-deficient adult mice and embryos expressing a catalytically inactive RASA1R780Q mutation. Thus, RASA1 catalytic activity is essential for the function and develop...

American Journal of Clinical and Experimental Immunology, 2012

T cell receptor-induced activation of the Ras signaling pathway is essential for T cell developme... more T cell receptor-induced activation of the Ras signaling pathway is essential for T cell development, proliferation and differentiation. Given the central role of Ras in T cell biology its activation must be tightly regulated. However, precisely how Ras activation is controlled in T cells is not completely understood. In this review, we provide a summary of the known factors and mechanisms involved in positive and negative regulation of Ras activation in the T cell lineage.

Advances in Experimental Medicine and Biology, 1993

Dendritic cells (DC) are identified both by morphology and function (1-3). These cells are locali... more Dendritic cells (DC) are identified both by morphology and function (1-3). These cells are localised to T cell micro-environments and are the most potent known accessory inducer cells for T cell responses. Even when there is heterogeneity in in vitro comparative accessory cell function (i. e. when more than one cell type can present), then the DC almost invariably prove to be the most potent relative inducers (4, 5). Thus the distinguishing molecular mechanisms involved in DC — T cell interaction that might account for this distinctive inducer capacity is obviously of considerable interest.

Encyclopedia of Signaling Molecules, 2012

The American journal of pathology, 2014

Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascula... more Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant blood vascular (BV) disorder characterized by CM and fast flow BV lesions. Inactivating mutations of the RASA1 gene are the cause of CM-AVM in most cases. RASA1 is a GTPase-activating protein that acts as a negative regulator of the Ras small GTP-binding protein. In addition, RASA1 performs Ras-independent functions in intracellular signal transduction. Whether CM-AVM results from loss of an ability of RASA1 to regulate Ras or loss of a Ras-independent function of RASA1 is unknown. To address this, we generated Rasa1 knockin mice with an R780Q point mutation that abrogates RASA1 catalytic activity specifically. Homozygous Rasa1(R780Q/R780Q) mice showed the same severe BV abnormalities as Rasa1-null mice and died midgestation. This finding indicates that BV abnormalities in CM-AVM develop as a result of loss of an ability of RASA1 to control Ras activation and not loss of a Ras-independent function of...

Trends in cardiovascular medicine, 2014

A number of genetic diseases in man have been described in which abnormalities in the development... more A number of genetic diseases in man have been described in which abnormalities in the development and function of the lymphatic vascular (LV) system are prominent features. The genes that are mutated in these diseases are varied and include genes that encode lymphatic endothelial cell (LEC) growth factor receptors and their ligands and transcription factors that control LEC fate and function. In addition, an increasing number of genes have been identified that encode components of the Ras signal transduction pathway that conveys signals from cell surface receptors to regulate cell growth, proliferation, and differentiation. Gene targeting studies performed in mice have confirmed that the LV system is particularly susceptible to perturbations in the Ras pathway.

Current opinion in investigational drugs (London, England : 2000), 2004

Systemic lupus erythematosus (SLE) is a prevalent, non-organ-specific autoimmune disease that is ... more Systemic lupus erythematosus (SLE) is a prevalent, non-organ-specific autoimmune disease that is partially caused by genetic factors. Types of genetic factors that can contribute to lupus have been revealed by studies of naturally occurring and genetically engineered mutant mice which are susceptible to this disease. Notably, a number of mutant mice have been reported that point to defective T-lymphocyte signal transduction as one potential cause of lupus. Deficient expression of adapter proteins, cell cycle control proteins, ubiquitin ligases and transcription factors, and impaired phosphatidylinositol 3-kinase (PI3-kinase) and Ras signaling in T-cells, all promote lupus in mice. These findings have important implications for the causes and treatment of human SLE.

Encyclopedia of Signaling Molecules, 2012

Disease models & mechanisms, 2011

SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for s... more SHP-2 (encoded by PTPN11) is a ubiquitously expressed protein tyrosine phosphatase required for signal transduction by multiple different cell surface receptors. Humans with germline SHP-2 mutations develop Noonan syndrome or LEOPARD syndrome, which are characterized by cardiovascular, neurological and skeletal abnormalities. To study how SHP-2 regulates tissue homeostasis in normal adults, we used a conditional SHP-2 mouse mutant in which loss of expression of SHP-2 was induced in multiple tissues in response to drug administration. Induced deletion of SHP-2 resulted in impaired hematopoiesis, weight loss and lethality. Most strikingly, induced SHP-2-deficient mice developed severe skeletal abnormalities, including kyphoses and scolioses of the spine. Skeletal malformations were associated with alterations in cartilage and a marked increase in trabecular bone mass. Osteoclasts were essentially absent from the bones of SHP-2-deficient mice, thus accounting for the osteopetrotic phen...

Bone, 2014

Src homology-2 protein tyrosine phosphatase (SHP-2) that is encoded by the PTPN11 gene in humans ... more Src homology-2 protein tyrosine phosphatase (SHP-2) that is encoded by the PTPN11 gene in humans is an intracellular signaling molecule that couples growth factor receptors to activation of the Ras small GTP-binding protein that regulates cell growth, proliferation and differentiation. Germline mutations of PTPN11 are causative of Noonan syndrome and LEOPARD syndrome in humans in which there are recognized skeletal abnormalities that include growth retardation, spinal curvature and chest malformations. In addition, combined somatic and germline PTPN11 mutations have been shown to be responsible for a rare benign bone cartilaginous tumor disease known as metachondromatosis. In parallel, gene targeting studies performed in mice have revealed an essential role for SHP-2 as a regulator of bone and skeletal development. In this review the significance of these findings in mice to the understanding of the pathogenesis of skeletal abnormalities in humans with SHP-2 mutations is discussed.

Advances in Experimental Medicine and Biology

... J. Drappa, LA Kamen, E. Chan, M. Georgiev, D. Ashany, F. Marti, and PD King, Impaired T cell ... more ... J. Drappa, LA Kamen, E. Chan, M. Georgiev, D. Ashany, F. Marti, and PD King, Impaired T cell death and lupus-like autoimmunity in T cell ... KZ Dai, HF Harbo, EG Celius, A. Oturai, PS Sorensen, LP Ryder, P. Datta, A. Svejgaard, J. Hillert, S. Fredrikson, M. Sandberg-Wollheim, M ...