The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions (original) (raw)
Related papers
Cell Communication and Adhesion, 1998
Microinjection and scrape-loading have been used to load cells in culture with soluble protein tyrosine phosphatases (FTPs). The introduction of protein tyrosine phosphatases into cells caused a rapid (within 5 minutes) decrease in tyrosine phosphorylation of major tyrosine phosphorylated substrates, including the focal adhesion kinase and paxillin. This decrease was detected both by blotting whole cell lysates with anti-phosphotyrosine antibodies and visualizing the phosphotyrosine in focal adhesions by immunofluorescence microscopy. After 30 minutes, many of the cells injected with tyrosine phosphatases revealed disruption of focal adhesions and stress fibers. To determine whether this disruption was due to the dephosphorylation of FAK and its substrates in focal adhesions, we have compared the effects of protein tyrosine phosphatase microinjection with the effects of displacing FAK from focal adhesions by microinjection of a dominant negative FAK construct. Although both procedures resulted in a marked decrease in the level of phosphotyrosine in focal adhesions, disruption of focal adhesions and stress fibers only occurred in cells loaded with exogenous protein tyrosine phosphatases. These results lead us to conclude that although tyrosine phosphorylation regulates focal adhesion and stress fiber stability, this does not involve FAK nor does it appear to involve tyrosine-phosphorylated proteins within focal adhesions. The critical tyrosine phosphorylation event is upstream of focal adhesions, a likely target being in the Rho pathway that regulates the formation of stress fibers and focal adhesions.
Regulation of Cell Adhesion by Protein-tyrosine Phosphatases: I. CELL-MATRIX ADHESION
Journal of Biological Chemistry, 2006
Protein-tyrosine phosphatases are key regulators of protein tyrosine phosphorylation. More than merely terminating the pathways initiated by protein-tyrosine kinases, phosphatases are active participants in many signaling pathways. Signals involving tyrosine phosphorylation are frequently generated in response to cell-matrix adhesion. In addition, high levels of protein tyrosine phosphorylation generally promote disassembly or turnover of adhesions. In this brief review, we will discuss the role of protein-tyrosine phosphatases in cell-matrix adhesions. Cell adhesion and migration are two tightly coupled processes critical to normal development and physiology. Two types of adhesion are usually distinguished: adhesion of cells to the underlying extracellular matrix (ECM) 3 and adhesion between adjacent cells. This review will focus on the former. Adhesions are more than simple physical links to the matrix or to other cells; they are also sites where signals are initiated, allowing cells to monitor their immediate environment. Prominent among the signaling pathways that emanate from adhesion sites are those involving protein tyrosine phosphorylation. The differential tyrosine phosphorylation of cell adhesion molecules and their associated proteins is one means of altering the assembly and stability of adhesions. Tyrosine phosphorylation status reflects the balance between protein-tyrosine kinases (PTKs) and protein-tyrosine phosphatases (PTPs). PTPs were discovered several years after PTKs and have been studied less extensively. However, the number of genes encoding PTPs rivals that of PTKs, suggesting that the functions of PTPs may be just as complex (1). In addition, the diversity of phenotypes in knockout mice lacking various PTP genes demonstrates that many PTPs have non-redundant functions. Several families of PTPs have been identified, including classical PTPs, dual specificity PTPs, myotubularins, PTEN-related PTPs, and aspartic acid-based PTPs (2). In this review, we will focus primarily on the classical PTPs and their functions in cell-matrix adhesion; the role of PTPs in cell-cell adhesions will be covered in a subsequent review (3). Classical PTPs contain a highly conserved catalytic domain with a critical cysteine sulfhydryl in the catalytic site. They show considerable diversity in their other domains, allowing for variations in binding partners, localization, and function. In humans, 38 classical PTPs have been identified and these fall into two groups, either transmembrane receptor-type PTPs (RPTPs) or cytoplasmic PTPs (2). RPTPs contain extracellular domains often resembling adhesion receptors and either single or tandem catalytic domains in the intracellular sequence. Cytoplasmic PTPs consist of a single catalytic domain with various amino-or carboxyl-terminal protein-binding motifs such as SH2 or FERM domains that serve targeting or regulatory roles.
Cell-cell adhesion medi-ated by a receptor-like protein tyrosine phosphatase
1993
Receptor-like protein tyrosine phosphatases (receptor-PTPs) represent a novel family of transmembrane proteins that are thought to play important roles in cellular regulation. They consist of a cytoplasmic catalytic region, a single transmembrane segment and an extracellular, putative ligand-binding domain, but the nature of their physiological ligands is unknown. We have recently cloned a new receptor-PTP (RPTPp), the ectodomain of which includes an Ig-like and four fibronectin type 111-like domains, suggesting that RPTPp may be involved in cell-cell or cell-matrix interactions.
Journal of Biological Chemistry, 2008
PTPD1 is a cytosolic nonreceptor tyrosine phosphatase and a positive regulator of the Src-epidermal growth factor transduction pathway. We show that PTPD1 localizes along actin filaments and at adhesion plaques. PTPD1 forms a stable complex via distinct molecular modules with actin, Src tyrosine kinase, and focal adhesion kinase (FAK), a scaffold protein kinase enriched at adhesion plaques. Overexpression of PTPD1 promoted cell scattering and migration, short hairpin RNA-mediated silencing of endogenous PTPD1, or expression of PTPD1 mutants lacking either catalytic activity (PTPD1 C1108S ) or the FERM domain (PTPD1 ⌬1-325 ) significantly reduced cell motility. PTPD1 and Src catalytic activities were both required for epidermal growth factor-induced FAK autophosphorylation at its active site and for downstream propagation of ERK1/2 signaling. Our findings demonstrate that PTPD1 is a component of a multivalent scaffold complex nucleated by FAK at specific intracellular sites. By modulating Src-FAK signaling at adhesion sites, PTPD1 promotes the cytoskeleton events that induce cell adhesion and migration.
Liprins, a Family of LAR Transmembrane Protein-tyrosine Phosphatase-interacting Proteins
Journal of Biological Chemistry, 1998
LAR family transmembrane protein-tyrosine phosphatases function in axon guidance and mammary gland development. In cultured cells, LAR binds to the intracellular, coiled coil LAR-interacting protein at discrete ends of focal adhesions, implicating these proteins in the regulation of cell-matrix interactions. We describe seven LAR-interacting protein-like genes in humans and Caenorhabditis elegans that form the liprin gene family. Based on sequence similarities and binding characteristics, liprins are subdivided into ␣-type and -type liprins. The C-terminal, non-coiled coil regions of ␣-liprins bind to the membrane-distal phosphatase domains of LAR family members, as well as to the C-terminal, non-coiled coil region of -liprins. Both ␣and -liprins homodimerize via their N-terminal, coiled coil regions. Liprins are thus multivalent proteins that potentially form complex structures. Some liprins have broad mRNA tissue distributions, whereas others are predominately expressed in the brain. Co-expression studies indicate that liprin-␣2 alters LAR cellular localization and induces LAR clustering. We propose that liprins function to localize LAR family tyrosine phosphatases at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates.