Genomes and Genes
focal adhesion kinase 2
Summary: A non-receptor protein-tyrosine kinase that is expressed primarily in the BRAIN; OSTEOBLASTS; and LYMPHOID CELLS. In the CENTRAL NERVOUS SYSTEM focal adhesion kinase 2 modulates ION CHANNEL function and MITOGEN-ACTIVATED PROTEIN KINASES activity.
- Bongiorno Borbone L, Onofri F, Giovedi S, Ferrari R, Girault J, Benfenati F. The translocation of focal adhesion kinase in brain synaptosomes is regulated by phosphorylation and actin assembly. J Neurochem. 2002;81:1212-22 pubmed
- Calle Y, Carragher N, Thrasher A, Jones G. Inhibition of calpain stabilises podosomes and impairs dendritic cell motility. J Cell Sci. 2006;119:2375-85 pubmed..In summary, our results provide evidence that calpain regulates podosome composition and turnover and that this process is required for efficient migration of dendritic cells. ..
- Alier K, Morris B. Divergent regulation of Pyk2/CAKbeta phosphorylation by Ca2+ and cAMP in the hippocampus. Biochim Biophys Acta. 2005;1745:342-9 pubmed..These results implicate Ca2+ and multiple forms of PKC in the activation of Pyk2 downstream of NMDA receptors and suggest that cAMP-dependent processes exert a suppressive action on Pyk2. ..
- Park S, Avraham H, Avraham S. RAFTK/Pyk2 activation is mediated by trans-acting autophosphorylation in a Src-independent manner. J Biol Chem. 2004;279:33315-22 pubmed..Taken together, these studies provide insights into the molecular mechanism of RAFTK autophosphorylation and the specific role of Src in the regulation of RAFTK activation. ..
- Rucci N, Ricevuto E, Ficorella C, Longo M, Perez M, Di Giacinto C, et al. In vivo bone metastases, osteoclastogenic ability, and phenotypic characterization of human breast cancer cells. Bone. 2004;34:697-709 pubmed..Therefore, we believe that reduced aggressiveness of breast carcinomas could correlate with a greater osteolytic activity featuring their bone metastases. ..
- Shi C, Kehrl J. Pyk2 amplifies epidermal growth factor and c-Src-induced Stat3 activation. J Biol Chem. 2004;279:17224-31 pubmed..These results indicate that Pyk2 facilitates EGFR- and c-Src-mediated Stat3 activation, thereby implicating Pyk2 activation as a potential co-mediator in triggering Stat3-induced oncogenesis. ..
- Kruljac Letunic A, Moelleken J, Kallin A, Wieland F, Blaukat A. The tyrosine kinase Pyk2 regulates Arf1 activity by phosphorylation and inhibition of the Arf-GTPase-activating protein ASAP1. J Biol Chem. 2003;278:29560-70 pubmed..We therefore provide evidence for a functional interaction between Pyk2 and ASAP1 and a regulation of ASAP1 and hence Arf1 activity by Pyk2-mediated tyrosine phosphorylation. ..
- Orr A, Murphy Ullrich J. Regulation of endothelial cell function BY FAK and PYK2. Front Biosci. 2004;9:1254-66 pubmed..This review will explore the current understanding of FAK and Pyk2 signaling in endothelial regulation of vascular function. ..
- Sancho D, Montoya M, Monjas A, Gordón Alonso M, Katagiri T, Gil D, et al. TCR engagement induces proline-rich tyrosine kinase-2 (Pyk2) translocation to the T cell-APC interface independently of Pyk2 activity and in an immunoreceptor tyrosine-based activation motif-mediated fashion. J Immunol. 2002;169:292-300 pubmed..All these data suggest that, by translocating to the vicinity of the immune synapse, Pyk2 could play an essential role in T cell activation and polarized secretion of cytokines. ..
- Block E, Tolino M, Klarlund J. Pyk2 activation triggers epidermal growth factor receptor signaling and cell motility after wounding sheets of epithelial cells. J Biol Chem. 2010;285:13372-9 pubmed publisher..In wound healing studies, Pyk2 small interfering RNA or dominant negative inhibited cell migration. These results show that activation of Pyk2 is an early signal that promotes wound healing by stimulating the SFK/EGFR signaling pathway. ..
- Collins M, Tremblay M, Chapman N, Curtiss M, Rothman P, Houtman J. The T cell receptor-mediated phosphorylation of Pyk2 tyrosines 402 and 580 occurs via a distinct mechanism than other receptor systems. J Leukoc Biol. 2010;87:691-701 pubmed publisher..Together, these data have defined more fully the mechanism for the TCR-induced phosphorylation of specific sites on Pyk2, suggesting that the TCR has a distinct pathway for the activation of Pyk2 compared with other receptor systems. ..
- Xi C, Xiong F, Zhou Z, Mei L, Xiong W. PYK2 interacts with MyD88 and regulates MyD88-mediated NF-kappaB activation in macrophages. J Leukoc Biol. 2010;87:415-23 pubmed publisher..These results suggest that via interaction with MyD88, PYK2 is involved in modulating cytokine (e.g., LPS) stimulation of NF-kappaB activity and signaling, providing a mechanism underlying PYK2 regulation of an inflammatory response. ..
- Han S, Mistry A, Chang J, Cunningham D, Griffor M, Bonnette P, et al. Structural characterization of proline-rich tyrosine kinase 2 (PYK2) reveals a unique (DFG-out) conformation and enables inhibitor design. J Biol Chem. 2009;284:13193-201 pubmed publisher..Our structural, biophysical, and pharmacological studies suggest that the unique features of the DFG motif, including Leu-504 hinge-loop variability, can be exploited for the development of selective protein kinase inhibitors. ..
- Han H, Fuortes M, Nathan C. Critical role of the carboxyl terminus of proline-rich tyrosine kinase (Pyk2) in the activation of human neutrophils by tumor necrosis factor: separation of signals for the respiratory burst and degranulation. J Exp Med. 2003;197:63-75 pubmed..Inhibition of select inflammatory functions without impairment of antibacterial activity may commend the Pyk2 pathway as a potential target for antiinflammatory therapy. ..
- Zhang S, Guo D, Jiang L, Zhang Q, Qiu X, Wang E. SOCS3 inhibiting migration of A549 cells correlates with PYK2 signaling in vitro. BMC Cancer. 2008;8:150 pubmed publisher..These results also suggest a negative role of SOCS3 in PYK2 signaling, and a previously unidentified regulatory mechanism for PYK2 function. ..
- Fisslthaler B, Loot A, Mohamed A, Busse R, Fleming I. Inhibition of endothelial nitric oxide synthase activity by proline-rich tyrosine kinase 2 in response to fluid shear stress and insulin. Circ Res. 2008;102:1520-8 pubmed publisher..The PYK2-dependent inhibition of NO production may serve to keep eNOS activity low and limit the detrimental consequences of maintained high NO output, ie, the generation of peroxynitrite. ..
- Allingham M, van Buul J, Burridge K. ICAM-1-mediated, Src- and Pyk2-dependent vascular endothelial cadherin tyrosine phosphorylation is required for leukocyte transendothelial migration. J Immunol. 2007;179:4053-64 pubmed..7 +/- 7.1% and 38.8 +/- 6.5% reduction, respectively). Our results demonstrate that engagement of ICAM-1 by leukocytes results in tyrosine phosphorylation of VE-cadherin, which is required for efficient neutrophil TEM. ..
- Okigaki M, Davis C, Falasca M, Harroch S, Felsenfeld D, Sheetz M, et al. Pyk2 regulates multiple signaling events crucial for macrophage morphology and migration. Proc Natl Acad Sci U S A. 2003;100:10740-5 pubmed..These experiments reveal a role for Pyk2 in cell signaling in macrophages essential for cell migration and function. ..
- Taniyama Y, Weber D, Rocic P, Hilenski L, Akers M, Park J, et al. Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. Mol Cell Biol. 2003;23:8019-29 pubmed..These observations identify a novel interaction between PDK1 and Pyk2 that regulates the integrity of focal adhesions, which are major compartments for integrating signals for cell growth, apoptosis, and migration. ..
- Melikova S, Dylla S, Verfaillie C. Phosphatidylinositol-3-kinase activation mediates proline-rich tyrosine kinase 2 phosphorylation and recruitment to beta1-integrins in human CD34+ cells. Exp Hematol. 2004;32:1051-6 pubmed..Activation of PI3K following beta1-integrin engagement on human CD34+ cells results in subsequent phosphorylation of PYK2, and is required for the recruitment of the PI3K/PYK2 complex to beta1-integrins at the cell surface. ..
- St Pierre J, Lysechko T, Ostergaard H. Hypophosphorylated and inactive Pyk2 associates with paxillin at the microtubule organizing center in hematopoietic cells. Cell Signal. 2011;23:718-30 pubmed publisher..We hypothesize that a reservoir of primarily inactive Pyk2 associates with paxillin at the MTOC, which may allow for rapid delivery of Pyk2 to specific sites of adhesion. ..
- Gao C, Blystone S. A Pyk2-Vav1 complex is recruited to beta3-adhesion sites to initiate Rho activation. Biochem J. 2009;420:49-56 pubmed publisher..These results indicate that Pyk2 is a critical signalling molecule downstream of beta3 integrin tyrosine phosphorylation and mediates Vav1 recruitment to accomplish actin reorganization necessary for adhesion. ..
- Anand A, Prasad A, Bradley R, Deol Y, Nagaraja T, Ren X, et al. HIV-1 gp120-induced migration of dendritic cells is regulated by a novel kinase cascade involving Pyk2, p38 MAP kinase, and LSP1. Blood. 2009;114:3588-600 pubmed publisher..Taken together, our studies provide an insight into a novel gp120-mediated pathway that regulates DC chemotaxis and contributes to the dissemination of HIV-1 within an infected person. ..
- Fernandis A, Prasad A, Band H, Klösel R, Ganju R. Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells. Oncogene. 2004;23:157-67 pubmed..We also observed the activation of matrix metalloproteinases 2 and 9 upon CXCL12 stimulation. These studies provide new information regarding signaling pathways that may regulate CXCL12-induced metastasis in breast cancer cells. ..
- Owen K, Pixley F, Thomas K, Vicente Manzanares M, Ray B, Horwitz A, et al. Regulation of lamellipodial persistence, adhesion turnover, and motility in macrophages by focal adhesion kinase. J Cell Biol. 2007;179:1275-87 pubmed..However, the combined loss of FAK and Pyk2 had no greater effect than the loss of either molecule alone, indicating that both kinases function within the same pathway to promote invasion. ..
- Kohno T, Matsuda E, Sasaki H, Sasaki T. Protein-tyrosine kinase CAKbeta/PYK2 is activated by binding Ca2+/calmodulin to FERM F2 alpha2 helix and thus forming its dimer. Biochem J. 2008;410:513-23 pubmed..Our results indicate that Ca2+/calmodulin binding to the FERM F2-alpha2 helix of CAKbeta/PYK2 releases its kinase domain from autoinhibition by forming a dimer. ..
- Matsui A, Okigaki M, Amano K, Adachi Y, Jin D, Takai S, et al. Central role of calcium-dependent tyrosine kinase PYK2 in endothelial nitric oxide synthase-mediated angiogenic response and vascular function. Circulation. 2007;116:1041-51 pubmed
- Wong N, Lai J, Maeshima N, Johnson P. CD44-mediated elongated T cell spreading requires Pyk2 activation by Src family kinases, extracellular calcium, phospholipase C and phosphatidylinositol-3 kinase. Cell Signal. 2011;23:812-9 pubmed publisher..Together this demonstrates that multiple factors are required for CD44-induced Pyk2 activation, which plays a critical role in CD44-mediated elongated T cell spreading. ..
- van Buul J, Anthony E, Fernandez Borja M, Burridge K, Hordijk P. Proline-rich tyrosine kinase 2 (Pyk2) mediates vascular endothelial-cadherin-based cell-cell adhesion by regulating beta-catenin tyrosine phosphorylation. J Biol Chem. 2005;280:21129-36 pubmed..This signaling is initiated upon loss of VE-cadherin function and is important for our insight in the modulation of endothelial integrity. ..
- Zanin Zhorov A, Tal G, Shivtiel S, Cohen M, Lapidot T, Nussbaum G, et al. Heat shock protein 60 activates cytokine-associated negative regulator suppressor of cytokine signaling 3 in T cells: effects on signaling, chemotaxis, and inflammation. J Immunol. 2005;175:276-85 pubmed..These effects of HSP60 could not be attributed to LPS or LPS-associated lipoprotein contamination. Thus, HSP60 can regulate T cell-mediated inflammation via specific signal transduction and SOCS3 activation. ..
- Lipinski C, Tran N, Bay C, Kloss J, McDonough W, Beaudry C, et al. Differential role of proline-rich tyrosine kinase 2 and focal adhesion kinase in determining glioblastoma migration and proliferation. Mol Cancer Res. 2003;1:323-32 pubmed..These data suggest that FAK and Pyk2 function as important signaling effectors in gliomas and indicate that their differential regulation may be determining factors in the temporal development of proliferative or migrational phenotypes. ..
- Yuan T, Lin F, Veeramani S, Chen S, Earp H, Lin M. ErbB-2 via PYK2 upregulates the adhesive ability of androgen receptor-positive human prostate cancer cells. Oncogene. 2007;26:7552-9 pubmed..In summary, our data suggested that ErbB-2, via PYK2-ERK/MAPK, upregulates the adhesive ability of AR-positive human PCa cells. ..
- van der Horst E, Weber I, Ullrich A. Tyrosine phosphorylation of PYK2 mediates heregulin-induced glioma invasion: novel heregulin/HER3-stimulated signaling pathway in glioma. Int J Cancer. 2005;113:689-98 pubmed..These results suggest a novel Heregulin/HER3-stimulated signaling pathway in glioblastoma-derived cell lines that involves phosphorylation of PYK2 and mediates invasiveness of glioma cells. ..
- Lipinski C, Loftus J. Targeting Pyk2 for therapeutic intervention. Expert Opin Ther Targets. 2010;14:95-108 pubmed publisher..Thus, approaches that inhibit the effector function of Pyk2 by targeting regulatory modules can increase specificity and will be a welcome asset to the therapeutic arena. ..
- Gutenberg A, Bruck W, Buchfelder M, Ludwig H. Expression of tyrosine kinases FAK and Pyk2 in 331 human astrocytomas. Acta Neuropathol. 2004;108:224-30 pubmed..This connection and the roles of these two tyrosine kinases in the progression of tumors should be confirmed by further studies. ..
- Bagi C, Christensen J, Cohen D, Roberts W, Wilkie D, Swanson T, et al. Sunitinib and PF-562,271 (FAK/Pyk2 inhibitor) effectively block growth and recovery of human hepatocellular carcinoma in a rat xenograft model. Cancer Biol Ther. 2009;8:856-65 pubmed
- Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne W, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004;279:17660-6 pubmed
- Paulino V, Yang Z, Kloss J, Ennis M, Armstrong B, Loftus J, et al. TROY (TNFRSF19) is overexpressed in advanced glial tumors and promotes glioblastoma cell invasion via Pyk2-Rac1 signaling. Mol Cancer Res. 2010;8:1558-67 pubmed publisher..These findings position aberrant expression and/or signaling by TROY as a contributor, and possibly as a driver, of the malignant dispersion of glioma cells. ..
- Boutahar N, Guignandon A, Vico L, Lafage Proust M. Mechanical strain on osteoblasts activates autophosphorylation of focal adhesion kinase and proline-rich tyrosine kinase 2 tyrosine sites involved in ERK activation. J Biol Chem. 2004;279:30588-99 pubmed..The latter was induced by ERK2 phosphorylation under the control of FAK and PYK2 phosphorylation orchestrated in a time-dependent manner. ..
- Tai L, Okuda M, Abe J, Yan C, Berk B. Fluid shear stress activates proline-rich tyrosine kinase via reactive oxygen species-dependent pathway. Arterioscler Thromb Vasc Biol. 2002;22:1790-6 pubmed..These results show a redox-sensitive pathway for flow-mediated activation of nonreceptor tyrosine kinase activity that requires ROS and intracellular calcium, but not Src kinase. ..
- Lakkakorpi P, Bett A, Lipfert L, Rodan G, Duong L. PYK2 autophosphorylation, but not kinase activity, is necessary for adhesion-induced association with c-Src, osteoclast spreading, and bone resorption. J Biol Chem. 2003;278:11502-12 pubmed..We thus concluded that phosphorylation at Tyr-402 in PYK2 is essential in the regulation of adhesion-dependent cytoskeletal organization in osteoclasts. ..
- Rufanova V, Alexanian A, Wakatsuki T, Lerner A, Sorokin A. Pyk2 mediates endothelin-1 signaling via p130Cas/BCAR3 cascade and regulates human glomerular mesangial cell adhesion and spreading. J Cell Physiol. 2009;219:45-56 pubmed publisher..Our data suggest that ET-1 stimulated the GTPase Rap1 (but neither RhoA nor Ras) by a mechanism involving Pyk2 activation and recruitment of the p130Cas/BCAR3 complex in GMC. ..
- Sun C, Man K, Ng K, Ho J, Lim Z, Cheng Q, et al. Proline-rich tyrosine kinase 2 (Pyk2) promotes proliferation and invasiveness of hepatocellular carcinoma cells through c-Src/ERK activation. Carcinogenesis. 2008;29:2096-105 pubmed publisher..In conclusion, our results showed that Pyk2 promoted cell proliferation and invasiveness by upregulation of the c-Src and ERK/MAPK-signaling pathways. ..
- Ying W, Aaron K, Sanders P. Mechanism of dietary salt-mediated increase in intravascular production of TGF-beta1. Am J Physiol Renal Physiol. 2008;295:F406-14 pubmed publisher..The experiments defined the molecular signaling events that promoted the production of TGF-beta1, a key growth factor involved in the vascular response to increased salt intake. ..
- Yano H, Mazaki Y, Kurokawa K, Hanks S, Matsuda M, Sabe H. Roles played by a subset of integrin signaling molecules in cadherin-based cell-cell adhesion. J Cell Biol. 2004;166:283-95 pubmed..Our analyses simultaneously exemplified the essential role of Fak in the maintenance of cell-cell adhesions in collective cell migration, a type of migration occurring in embryonic development and carcinoma invasion. ..
- Avraham H, Lee T, Koh Y, Kim T, Jiang S, Sussman M, et al. Vascular endothelial growth factor regulates focal adhesion assembly in human brain microvascular endothelial cells through activation of the focal adhesion kinase and related adhesion focal tyrosine kinase. J Biol Chem. 2003;278:36661-8 pubmed..Thus, these studies define a mechanism for the regulatory role of VEGF in focal adhesion complex assembly in HBMECs via activation of FAK and RAFTK/Pyk2. ..
- Guignandon A, Boutahar N, Rattner A, Vico L, Lafage Proust M. Cyclic strain promotes shuttling of PYK2/Hic-5 complex from focal contacts in osteoblast-like cells. Biochem Biophys Res Commun. 2006;343:407-14 pubmed
- Bartelt R, Cruz Orcutt N, Collins M, Houtman J. Comparison of T cell receptor-induced proximal signaling and downstream functions in immortalized and primary T cells. PLoS ONE. 2009;4:e5430 pubmed publisher..Both Jurkat E6.1 and HuT78 T cells had distinct similarities and differences compared to APBTs. Both cell lines have advantages and disadvantages, which must be taken into account when choosing them as a model T cell line. ..
- Haglund K, Ivankovic Dikic I, Shimokawa N, Kruh G, Dikic I. Recruitment of Pyk2 and Cbl to lipid rafts mediates signals important for actin reorganization in growing neurites. J Cell Sci. 2004;117:2557-68 pubmed..Our results indicate that recruitment of Pyk2/Cbl complexes to lipid rafts participates in growth factor-induced regulation of the actin cytoskeleton in growing neurites. ..
- Lim Y, Lim S, Tomar A, Gardel M, Bernard Trifilo J, Chen X, et al. PyK2 and FAK connections to p190Rho guanine nucleotide exchange factor regulate RhoA activity, focal adhesion formation, and cell motility. J Cell Biol. 2008;180:187-203 pubmed publisher..These studies elucidate a compensatory function for Pyk2 upon FAK loss and identify the FAK-p190RhoGEF complex as an important integrin-proximal regulator of FA formation during FN-stimulated cell motility. ..
- Loeser R, Forsyth C, Samarel A, Im H. Fibronectin fragment activation of proline-rich tyrosine kinase PYK2 mediates integrin signals regulating collagenase-3 expression by human chondrocytes through a protein kinase C-dependent pathway. J Biol Chem. 2003;278:24577-85 pubmed..studies have identified a novel pathway for the MAP kinase regulation of MMP-13 production which involves FN-f stimulation of the alpha5beta1 integrin and activation of the nonreceptor tyrosine kinase PYK2 by PKC, most likely PKCdelta ..