Koko Katagiri - Academia.edu (original) (raw)

Papers by Koko Katagiri

Research paper thumbnail of The M-Ras-RA-GEF-2-Rap1 Pathway Mediates Tumor Necrosis Factor-- dependent Regulation of Integrin Activation in Splenocytes

Research paper thumbnail of Rapl-mediated lymphocyte function-associated antigen-1 activation by the T cell antigen receptor is dependent on phospholipase C-γ1

The Journal of Biological Chemistry, 2004

Research paper thumbnail of The critical cytoplasmic regions of the αK/β2 integrin in Rap1-induced adhesion and migration

Molecular Biology of the Cell, 2003

Research paper thumbnail of Q and e values for several chain transfer agents

Journal of Polymer Science, 1955

Research paper thumbnail of The Critical Cytoplasmic Regions of the �L/�2 Integrin in Rap1-induced Adhesion and Migration

Mol Biol Cell, 2003

running title: cytoplasmic αL/β2 in Rap1 adhesion and migration Supplemental Material can be foun... more running title: cytoplasmic αL/β2 in Rap1 adhesion and migration Supplemental Material can be found at:

Research paper thumbnail of Relative reactivities of polymer radicals

Journal of Polymer Science, 1960

Research paper thumbnail of Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis

Nature Communications, 2015

Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high e... more Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high endothelial venule (HEV). Here we show that Rap1-GDP restrains rolling behaviours of T cells on the peripheral lymph node addressin (PNAd), P-selectin and mucosal addressin cell adhesion molecule-1 (MadCAM-1) by inhibiting tether formation. Consequently, Rap1 deficiency impairs homing of naive T cells to peripheral lymph nodes, but accelerates homing of TH17 and TH1 cells to the colon, resulting in spontaneous colitis with tumours. Rap1-GDP associates with and activates lymphocyte-oriented kinase, which phosphorylates ERM (ezrin, radixin and moesin) in resting T cells. Phosphomimetic ezrin reduces the rolling of Rap1-deficient cells, and thereby decreases their homing into the colon. On the other hand, chemokines activate Rap1 at the plasma membrane within seconds, and Rap1-GTP binds to filamins, which diminishes its association with the β2 chain of LFA-1 and results in LFA-1 activation. This Rap1-dependent regulation of T-cell circulation prevents the onset of colitis.

Research paper thumbnail of Chain transfer constants of polyethylene glycol and its dodecyl ether in radical polymerization

Journal of Polymer Science, 1960

Research paper thumbnail of Ubiquitin-proteasome system is involved in induction of LFA-1/ICAM-1-dependent adhesion of HL-60 cells

Journal of Leukocyte Biology, Jun 1, 1999

Membrane-permeable proteasome inhibitors, lactacystin (LC) and N-acetyl-Leu-Leu-norleucinal (ALLN... more Membrane-permeable proteasome inhibitors, lactacystin (LC) and N-acetyl-Leu-Leu-norleucinal (ALLN), but not calpain inhibitor Z-Leu-leucinal (ZLL), prevented LFA-1/ICAM-1-dependent cellular adhesion of TPA-stimulated HL-60 cells. These proteasome inhibitors affected neither the induction of monocytic differentiation nor the accompanying protein-tyrosine phosphorylation. They suppressed the increase in the avidity of LFA-1 to ICAM-1 without changing the expression of these molecules. Immunoblotting using monoclonal antibody FK-1, which reacts specifically with polyubiquitinated proteins, demonstrated that the proteasome inhibitors caused the drastic accumulation of the polyubiquitinated proteins in the membrane fraction of TPA-treated HL-60 cells. This indicates that accompanying activation of LFA-1, TPA induces the polyubiquitination of the membrane proteins, which are rapidly degraded by proteasomes. These data taken together show that proteolysis mediated by the ubiquitin-proteasome system is a prerequisite for the induction of LFA-1-dependent adhesion of HL-60 cells.

Research paper thumbnail of miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target

Scientific reports, Jan 12, 2016

The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is loc... more The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor...

Research paper thumbnail of The M-Ras-RA-GER-2-Rap1 pathway mediates tumor necrosis factor-α-dependent regulation of integrin activation in splenocytes

Molecular Biology of the Cell, 2007

Research paper thumbnail of Organizer-Like Reticular Stromal Cell Layer Common to Adult Secondary Lymphoid Organs1

cialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in t... more cialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established

Research paper thumbnail of Differential Regulation of Leukocyte Function-Associated Antigen-ll Intercellular Adhesion Molecules 1 Dependent Adhesion and Aggregation in HL60 Cells

SCAPING FROM severe infectious disease caused by E invading microorganisms depends on the ability... more SCAPING FROM severe infectious disease caused by E invading microorganisms depends on the ability of neutrophilic polymorphonuclear leukocytes (PMN) to adhere to the endothelium, emigrate into infected tissue, and kill bacteria.le3 These motile processes are driven by the activa- tion of integrins and the successive remodeling of the micro- filamentous system, including rapid interconversion of actin, the major component of

Research paper thumbnail of Remark on the paper by R. L. Herbst, Jr., and R. E. Martin, entitled “relative reactivities of polymer radicals in vinyl polymerizations”

Journal of Polymer Science, 1955

Herbst and Martin' find that the relative reactivities of polymer radicals can be described by th... more Herbst and Martin' find that the relative reactivities of polymer radicals can be described by the Q' and e constants of the parent monomers. I n our general opinion regarding copolymerization,2 a monomer of the styrene type, for instance, is reactive b u t its radical is rather stable, while, on the other hand, vinyl acetate is unreactive as the monomer and is unstable as the radical. This does not coincide with the conclusion of Herbst and Martin. Before we attempt to make these relations clear, it will be necessary to note that there is a discrepancy in their report. In of their article, Q' values are assumed to be the values of Q in Alfrey and Price's scheme, though Q' values defined by them as q/RT are not the same as Q defined as exp { -q / R T ] . Also the dimension of k, is not moles/l./sec., as stated in the same figure, but I./moles/sec.

Research paper thumbnail of Rab13 acts downstream of the kinase Mst1 to deliver the integrin LFA-1 to the cell surface for lymphocyte trafficking

Science signaling, Jan 29, 2014

In lymphocytes, the kinase Mst1 is required for the proper organization of integrins in the plasm... more In lymphocytes, the kinase Mst1 is required for the proper organization of integrins in the plasma membrane at the leading edge of migrating cells, which is critical for lymphocyte trafficking. We found a functional link between the small G protein Rab13 and Mst1 in lymphocyte adhesion and migration. In response to stimulation of T lymphocytes with chemokine, Mst1 promoted phosphorylation of the guanine nucleotide exchange factor DENND1C (differentially expressed in normal and neoplastic cells domain 1C), which activated Rab13. Active Rab13 associated with Mst1 to facilitate the delivery of the integrin LFA-1 (lymphocyte function-associated antigen 1) to the leading edge of lymphocytes. Delivery of LFA-1 involved the recruitment of myosin Va along actin filaments, which extended as a result of the localization of the actin regulatory protein VASP to the cell periphery through phosphorylation of VASP at Ser(157) by Mst1. Inhibition of Rab13 function reduced the adhesion and migration...

Research paper thumbnail of Differential regulation of leukocyte function-associated antigen-1/ intercellular adhesion molecules-1-dependent adhesion and aggregation in HL-60 cells

Blood, Jan 15, 1996

Activation of integrin and organization of cytoskeletal proteins are highly regulated in cell adh... more Activation of integrin and organization of cytoskeletal proteins are highly regulated in cell adhesion and aggregation. The interaction of leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecules-1 (ICAM-1) mediates cell adhesion and aggregation, which facilitate leukocyte trafficking to inflamed tissues and augment effector functions. We investigated how LFA-1/ICAM-1-mediated adhesion and aggregation are regulated in HL-60 cells induced to differentiate into neutrophils by retinoic acid (RA). Uninduced HL-60 cells did not bind to ICAM-1 even with stimulation by 12-0-tetradecanoyl phorbol-13-acetate, although they express LFA-1 on the cell surface. When cultured with RA for 24 hours, HL-60 cells were able to adhere to ICAM-1 constitutively. The induction of adhesion did not accompany any change in surface density of LFA-1, indicating that the avidity of LFA-1 was increased. The change in its avidity required de novo synthesis of proteins. Although ICAM-1 ...

Research paper thumbnail of Anti-Apoptotic Role of Protein-Tyrosine Kinases During Granulocytic Differentiation of HL-60 Cells

Bone Marrow Transplantation, 1996

Research paper thumbnail of Rap1 and Integrin Inside-Out Signaling

Methods in Molecular Biology, 2011

In leukocytes, integrins play important roles in adhesive interactions with endothelium, antigen-... more In leukocytes, integrins play important roles in adhesive interactions with endothelium, antigen-presenting cells, and effector functions such as cytotoxicity. This chapter describes methods to study Ras proximity 1 (Rap1), a signaling molecule that has been increasingly recognized as an important regulator of integrin-mediated cell adhesion in the immune system as well as hemostasis. Rap1 is activated by a wide variety of external stimuli including chemokines and antigens. Signaling via Rap1 transmits an inside-out signal to the integrins, thereby increasing adhesiveness to ligands such as immunoglobulin superfamily proteins as well as extracellular matrix proteins and plasma proteins. This process induces leukocyte cell adhesion to the endothelium and antigen-presenting cells. In addition to integrin regulation, activated Rap1 induces cell polarity of lymphocytes, which is coordinated with LFA-1 redistribution to the leading edge.

Research paper thumbnail of Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking

Nature Immunology, 2004

Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to gu... more Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to guide immune cell migration. However, the critical molecule for governing the high trafficking capability of immune cells is not clear. Here we show that the effector molecule RAPL is indispensable in the integrin-mediated adhesion and migration of lymphocytes and dendritic cells. RAPL deficiency caused defective chemokine-triggered lymphocyte adhesion and migration to secondary lymphoid organs, resulting in atrophic lymphoid follicles and deficient marginal zone B cells, concomitant with increased immature B cells in the blood. Furthermore, splenic dendritic cells were diminished and defective in adhesion. After being activated with inflammatory stimuli, skin and splenic dendritic cells failed to migrate into either the draining lymph nodes or the white pulp of the spleen. Thus, RAPL is a crucial immune cell trafficking regulator essential for immunosurveillance.

Research paper thumbnail of Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow

The Journal of Cell Biology, 2003

hemokines arrest circulating lymphocytes within the vasculature through the rapid up-regulation o... more hemokines arrest circulating lymphocytes within the vasculature through the rapid up-regulation of leukocyte integrin adhesive activity, promoting subsequent lymphocyte transmigration. However, the key regulatory molecules regulating this process have remained elusive. Here, we demonstrate that Rap1 plays a pivotal role in chemokine-induced integrin activation and migration. Rap1 was activated by secondary lymphoid tissue chemokine (SLC; CCL21) and stromal-derived factor 1 (CXCL4) treatment in lymphocytes within seconds. Inhibition of Rap1 by Spa1, a Rap1-specific GTPase-activating protein, abrogated chemokine-stimulated lymphocyte rapid adhesion to endo-C thelial cells under flow via intercellular adhesion molecule 1. Expression of a dominant active Rap1V12 in lymphocytes stimulated shear-resistant adhesion, robust cell migration on immobilized intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and transendothelial migration under flow. We also demonstrated that Rap1V12 expression in lymphocytes induced a polarized morphology, accompanied by the redistribution of CXCR4 and CD44 to the leading edge and uropod, respectively. Spa1 effectively suppressed this polarization after SLC treatment. This unique characteristic of Rap1 may control chemokineinduced lymphocyte extravasation.

Research paper thumbnail of The M-Ras-RA-GEF-2-Rap1 Pathway Mediates Tumor Necrosis Factor-- dependent Regulation of Integrin Activation in Splenocytes

Research paper thumbnail of Rapl-mediated lymphocyte function-associated antigen-1 activation by the T cell antigen receptor is dependent on phospholipase C-γ1

The Journal of Biological Chemistry, 2004

Research paper thumbnail of The critical cytoplasmic regions of the αK/β2 integrin in Rap1-induced adhesion and migration

Molecular Biology of the Cell, 2003

Research paper thumbnail of Q and e values for several chain transfer agents

Journal of Polymer Science, 1955

Research paper thumbnail of The Critical Cytoplasmic Regions of the �L/�2 Integrin in Rap1-induced Adhesion and Migration

Mol Biol Cell, 2003

running title: cytoplasmic αL/β2 in Rap1 adhesion and migration Supplemental Material can be foun... more running title: cytoplasmic αL/β2 in Rap1 adhesion and migration Supplemental Material can be found at:

Research paper thumbnail of Relative reactivities of polymer radicals

Journal of Polymer Science, 1960

Research paper thumbnail of Dual functions of Rap1 are crucial for T-cell homeostasis and prevention of spontaneous colitis

Nature Communications, 2015

Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high e... more Rap1-GTP activates leukocyte function-associated antigen-1 (LFA-1) to induce arrest on the high endothelial venule (HEV). Here we show that Rap1-GDP restrains rolling behaviours of T cells on the peripheral lymph node addressin (PNAd), P-selectin and mucosal addressin cell adhesion molecule-1 (MadCAM-1) by inhibiting tether formation. Consequently, Rap1 deficiency impairs homing of naive T cells to peripheral lymph nodes, but accelerates homing of TH17 and TH1 cells to the colon, resulting in spontaneous colitis with tumours. Rap1-GDP associates with and activates lymphocyte-oriented kinase, which phosphorylates ERM (ezrin, radixin and moesin) in resting T cells. Phosphomimetic ezrin reduces the rolling of Rap1-deficient cells, and thereby decreases their homing into the colon. On the other hand, chemokines activate Rap1 at the plasma membrane within seconds, and Rap1-GTP binds to filamins, which diminishes its association with the β2 chain of LFA-1 and results in LFA-1 activation. This Rap1-dependent regulation of T-cell circulation prevents the onset of colitis.

Research paper thumbnail of Chain transfer constants of polyethylene glycol and its dodecyl ether in radical polymerization

Journal of Polymer Science, 1960

Research paper thumbnail of Ubiquitin-proteasome system is involved in induction of LFA-1/ICAM-1-dependent adhesion of HL-60 cells

Journal of Leukocyte Biology, Jun 1, 1999

Membrane-permeable proteasome inhibitors, lactacystin (LC) and N-acetyl-Leu-Leu-norleucinal (ALLN... more Membrane-permeable proteasome inhibitors, lactacystin (LC) and N-acetyl-Leu-Leu-norleucinal (ALLN), but not calpain inhibitor Z-Leu-leucinal (ZLL), prevented LFA-1/ICAM-1-dependent cellular adhesion of TPA-stimulated HL-60 cells. These proteasome inhibitors affected neither the induction of monocytic differentiation nor the accompanying protein-tyrosine phosphorylation. They suppressed the increase in the avidity of LFA-1 to ICAM-1 without changing the expression of these molecules. Immunoblotting using monoclonal antibody FK-1, which reacts specifically with polyubiquitinated proteins, demonstrated that the proteasome inhibitors caused the drastic accumulation of the polyubiquitinated proteins in the membrane fraction of TPA-treated HL-60 cells. This indicates that accompanying activation of LFA-1, TPA induces the polyubiquitination of the membrane proteins, which are rapidly degraded by proteasomes. These data taken together show that proteolysis mediated by the ubiquitin-proteasome system is a prerequisite for the induction of LFA-1-dependent adhesion of HL-60 cells.

Research paper thumbnail of miR-133 regulates Evi1 expression in AML cells as a potential therapeutic target

Scientific reports, Jan 12, 2016

The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is loc... more The Ecotropic viral integration site 1 (Evi1) is a zinc finger transcription factor, which is located on chromosome 3q26, over-expression in some acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Elevated Evi1 expression in AML is associated with unfavorable prognosis. Therefore, Evi1 is one of the strong candidate in molecular target therapy for the leukemia. MicroRNAs (miRNAs) are small non-coding RNAs, vital to many cell functions that negatively regulate gene expression by translation or inducing sequence-specific degradation of target mRNAs. As a novel biologics, miRNAs is a promising therapeutic target due to its low toxicity and low cost. We screened miRNAs which down-regulate Evi1. miR-133 was identified to directly bind to Evi1 to regulate it. miR-133 increases drug sensitivity specifically in Evi1 expressing leukemic cells, but not in Evi1-non-expressing cells The results suggest that miR-133 can be promising therapeutic target for the Evi1 dysregulated poor...

Research paper thumbnail of The M-Ras-RA-GER-2-Rap1 pathway mediates tumor necrosis factor-α-dependent regulation of integrin activation in splenocytes

Molecular Biology of the Cell, 2007

Research paper thumbnail of Organizer-Like Reticular Stromal Cell Layer Common to Adult Secondary Lymphoid Organs1

cialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in t... more cialized stromal cells, designated lymphoid tissue organizer (LTo) in the embryonic anlagen; in the adult, several distinct stromal lineages construct elaborate tissue architecture and regulate lymphocyte compartmentalization. The relationship between the LTo and adult stromal cells, however, remains unclear, as does the precise number of stromal cell types that constitute mature SLOs are unclear. From mouse lymph nodes, we established

Research paper thumbnail of Differential Regulation of Leukocyte Function-Associated Antigen-ll Intercellular Adhesion Molecules 1 Dependent Adhesion and Aggregation in HL60 Cells

SCAPING FROM severe infectious disease caused by E invading microorganisms depends on the ability... more SCAPING FROM severe infectious disease caused by E invading microorganisms depends on the ability of neutrophilic polymorphonuclear leukocytes (PMN) to adhere to the endothelium, emigrate into infected tissue, and kill bacteria.le3 These motile processes are driven by the activa- tion of integrins and the successive remodeling of the micro- filamentous system, including rapid interconversion of actin, the major component of

Research paper thumbnail of Remark on the paper by R. L. Herbst, Jr., and R. E. Martin, entitled “relative reactivities of polymer radicals in vinyl polymerizations”

Journal of Polymer Science, 1955

Herbst and Martin' find that the relative reactivities of polymer radicals can be described by th... more Herbst and Martin' find that the relative reactivities of polymer radicals can be described by the Q' and e constants of the parent monomers. I n our general opinion regarding copolymerization,2 a monomer of the styrene type, for instance, is reactive b u t its radical is rather stable, while, on the other hand, vinyl acetate is unreactive as the monomer and is unstable as the radical. This does not coincide with the conclusion of Herbst and Martin. Before we attempt to make these relations clear, it will be necessary to note that there is a discrepancy in their report. In of their article, Q' values are assumed to be the values of Q in Alfrey and Price's scheme, though Q' values defined by them as q/RT are not the same as Q defined as exp { -q / R T ] . Also the dimension of k, is not moles/l./sec., as stated in the same figure, but I./moles/sec.

Research paper thumbnail of Rab13 acts downstream of the kinase Mst1 to deliver the integrin LFA-1 to the cell surface for lymphocyte trafficking

Science signaling, Jan 29, 2014

In lymphocytes, the kinase Mst1 is required for the proper organization of integrins in the plasm... more In lymphocytes, the kinase Mst1 is required for the proper organization of integrins in the plasma membrane at the leading edge of migrating cells, which is critical for lymphocyte trafficking. We found a functional link between the small G protein Rab13 and Mst1 in lymphocyte adhesion and migration. In response to stimulation of T lymphocytes with chemokine, Mst1 promoted phosphorylation of the guanine nucleotide exchange factor DENND1C (differentially expressed in normal and neoplastic cells domain 1C), which activated Rab13. Active Rab13 associated with Mst1 to facilitate the delivery of the integrin LFA-1 (lymphocyte function-associated antigen 1) to the leading edge of lymphocytes. Delivery of LFA-1 involved the recruitment of myosin Va along actin filaments, which extended as a result of the localization of the actin regulatory protein VASP to the cell periphery through phosphorylation of VASP at Ser(157) by Mst1. Inhibition of Rab13 function reduced the adhesion and migration...

Research paper thumbnail of Differential regulation of leukocyte function-associated antigen-1/ intercellular adhesion molecules-1-dependent adhesion and aggregation in HL-60 cells

Blood, Jan 15, 1996

Activation of integrin and organization of cytoskeletal proteins are highly regulated in cell adh... more Activation of integrin and organization of cytoskeletal proteins are highly regulated in cell adhesion and aggregation. The interaction of leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecules-1 (ICAM-1) mediates cell adhesion and aggregation, which facilitate leukocyte trafficking to inflamed tissues and augment effector functions. We investigated how LFA-1/ICAM-1-mediated adhesion and aggregation are regulated in HL-60 cells induced to differentiate into neutrophils by retinoic acid (RA). Uninduced HL-60 cells did not bind to ICAM-1 even with stimulation by 12-0-tetradecanoyl phorbol-13-acetate, although they express LFA-1 on the cell surface. When cultured with RA for 24 hours, HL-60 cells were able to adhere to ICAM-1 constitutively. The induction of adhesion did not accompany any change in surface density of LFA-1, indicating that the avidity of LFA-1 was increased. The change in its avidity required de novo synthesis of proteins. Although ICAM-1 ...

Research paper thumbnail of Anti-Apoptotic Role of Protein-Tyrosine Kinases During Granulocytic Differentiation of HL-60 Cells

Bone Marrow Transplantation, 1996

Research paper thumbnail of Rap1 and Integrin Inside-Out Signaling

Methods in Molecular Biology, 2011

In leukocytes, integrins play important roles in adhesive interactions with endothelium, antigen-... more In leukocytes, integrins play important roles in adhesive interactions with endothelium, antigen-presenting cells, and effector functions such as cytotoxicity. This chapter describes methods to study Ras proximity 1 (Rap1), a signaling molecule that has been increasingly recognized as an important regulator of integrin-mediated cell adhesion in the immune system as well as hemostasis. Rap1 is activated by a wide variety of external stimuli including chemokines and antigens. Signaling via Rap1 transmits an inside-out signal to the integrins, thereby increasing adhesiveness to ligands such as immunoglobulin superfamily proteins as well as extracellular matrix proteins and plasma proteins. This process induces leukocyte cell adhesion to the endothelium and antigen-presenting cells. In addition to integrin regulation, activated Rap1 induces cell polarity of lymphocytes, which is coordinated with LFA-1 redistribution to the leading edge.

Research paper thumbnail of Crucial functions of the Rap1 effector molecule RAPL in lymphocyte and dendritic cell trafficking

Nature Immunology, 2004

Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to gu... more Immunosurveillance requires the coordinated regulation of chemokines and adhesion molecules to guide immune cell migration. However, the critical molecule for governing the high trafficking capability of immune cells is not clear. Here we show that the effector molecule RAPL is indispensable in the integrin-mediated adhesion and migration of lymphocytes and dendritic cells. RAPL deficiency caused defective chemokine-triggered lymphocyte adhesion and migration to secondary lymphoid organs, resulting in atrophic lymphoid follicles and deficient marginal zone B cells, concomitant with increased immature B cells in the blood. Furthermore, splenic dendritic cells were diminished and defective in adhesion. After being activated with inflammatory stimuli, skin and splenic dendritic cells failed to migrate into either the draining lymph nodes or the white pulp of the spleen. Thus, RAPL is a crucial immune cell trafficking regulator essential for immunosurveillance.

Research paper thumbnail of Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow

The Journal of Cell Biology, 2003

hemokines arrest circulating lymphocytes within the vasculature through the rapid up-regulation o... more hemokines arrest circulating lymphocytes within the vasculature through the rapid up-regulation of leukocyte integrin adhesive activity, promoting subsequent lymphocyte transmigration. However, the key regulatory molecules regulating this process have remained elusive. Here, we demonstrate that Rap1 plays a pivotal role in chemokine-induced integrin activation and migration. Rap1 was activated by secondary lymphoid tissue chemokine (SLC; CCL21) and stromal-derived factor 1 (CXCL4) treatment in lymphocytes within seconds. Inhibition of Rap1 by Spa1, a Rap1-specific GTPase-activating protein, abrogated chemokine-stimulated lymphocyte rapid adhesion to endo-C thelial cells under flow via intercellular adhesion molecule 1. Expression of a dominant active Rap1V12 in lymphocytes stimulated shear-resistant adhesion, robust cell migration on immobilized intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and transendothelial migration under flow. We also demonstrated that Rap1V12 expression in lymphocytes induced a polarized morphology, accompanied by the redistribution of CXCR4 and CD44 to the leading edge and uropod, respectively. Spa1 effectively suppressed this polarization after SLC treatment. This unique characteristic of Rap1 may control chemokineinduced lymphocyte extravasation.