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Integrin Signaling (integrin + signaling)
Selected AbstractsBone Mineralization and Osteoblast Differentiation Are Negatively Modulated by Integrin ,v,3JOURNAL OF BONE AND MINERAL RESEARCH, Issue 2 2001Su-Li Cheng Abstract Numerous bone matrix proteins can interact with ,v-containing integrins including ,v,3. To elucidate the net effects of the interaction between these proteins and ,v,3 on osteoblast function, we developed a murine osteoblastic cell line that overexpressed human ,v,3. Human ,v,3-integrin was expressed on cell membrane, in which its presence did not alter the surface level of endogenous mouse ,v,3. The expressed human ,v,3 was functional because cell adhesion to osteopontin was increased and this increment was abolished by antibody against human ,v,3. The proliferation rate of cells overexpressing ,v,3 (,v,3-cells) was increased whereas matrix mineralization was decreased. To elucidate the mechanisms leading to inhibition of matrix mineralization, the expression of proteins important for mineralization was analyzed. Alkaline phosphatase activity and the expression of osteocalcin, type I collagen, and bone sialoprotein (BSP) were decreased whereas osteopontin was stimulated in ,v,3-cells. The regulation of osteopontin, osteocalcin, and BSP expression was mediated via transcriptional mechanism because their promoter activities were altered. Examination of molecules involved in integrin signaling indicated that activator protein-1 (AP-1) and extracellular signal-regulated kinase (Erk) activities were enhanced whereas c-jun N -terminal kinase (JNK) activity was decreased in ,v,3-cells. The activity of p38 and the levels of focal adhesion kinase (FAK) and vinculin were not altered. Moreover, the adhesions of ,v,3-cells to type I collagen and fibronectin were inhibited, which was attributed to decreased ,1-integrin levels on cell surface. In conclusion, overexpressing ,v,3-integrin in osteoblasts stimulated cell proliferation but retarded differentiation, which were derived via altered integrin-matrix interactions, signal transduction, and matrix protein expression. [source] Src and FAK mediate cell,matrix adhesion-dependent activation of met during transformation of breast epithelial cellsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2009Angela Y. Hui Abstract Cell,matrix adhesion has been shown to promote activation of the hepatocyte growth factor receptor, Met, in a ligand-independent manner. This process has been linked to transformation and tumorigenesis in a variety of cancer types. In the present report, we describe a key role of integrin signaling via the Src/FAK axis in the activation of Met in breast epithelial and carcinoma cells. Expression of an activated Src mutant in non-neoplastic breast epithelial cells or in carcinoma cells was found to increase phosphorylation of Met at regulatory tyrosines in the auto-activation loop domain, correlating with increased cell spreading and filopodia extensions. Furthermore, phosphorylated Met is complexed with ,1 integrins and is co-localized with vinculin and FAK at focal adhesions in epithelial cells expressing activated Src. Conversely, genetic or pharmacological inhibition of Src abrogates constitutive Met phosphorylation in carcinoma cells or epithelial cells expressing activated Src, and inhibits filopodia formation. Interestingly, Src-dependent phosphorylation of Met requires cell,matrix adhesion, as well as actin stress fiber assembly. Phosphorylation of FAK by Src is also required for Src-induced Met phosphorylation, emphasizing the importance of the Src/FAK signaling pathway. However, stimulation of Met phosphorylation by addition of exogenous HGF in epithelial cells is refractory to inhibition of Src family kinases, indicating that HGF-dependent and Src/integrin-dependent Met activation occur via distinct mechanisms. Together these findings demonstrate a novel mechanism by which the Src/FAK axis links signals from the integrin adhesion complex to promote Met activation in breast epithelial cells. J. Cell. Biochem. 107: 1168,1181, 2009. © 2009 Wiley-Liss, Inc. [source] Integrins mediate ,-amyloid-induced cell-cycle activation and neuronal deathJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2008Giuseppina Frasca Abstract Early intracellular events responsible for cell-cycle induction by ,-amyloid (A,) in neurons have not been identified yet. Extracellular signal,regulated kinases 1/2 (ERK1/2) have been identified in this pathway, and inhibition of ERK activity prevents cell-cycle activation and reduces neuronal death induced by A,. To identify upstream events responsible for ERK activation, attention has been focused on integrins. Treatment of SH-SY5Y cells, differentiated by long-term exposure to 10 ,M retinoic acid with a neutralizing anti-,1-integrin antibody significantly reduced A,-induced neuronal death. However, cell-cycle analysis showed that treatment with anti-,1-integrin per se produced changes in the distribution of cell populations, thus hampering any effect on A,-induced cell-cycle activation. 4-Amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4- D)pyramide, an inhibitor of src protein kinases that colocalizes with focal adhesion kinase (FAK) and is involved in integrin signaling, was effective in reducing activation of the cell cycle and preventing induction of neuronal death by A, while inhibiting ERK1/2 phosphorylation. Similar results were obtained when FAK expression was down-regulated by siRNA silencing. The present study identifies a sequence of early events in the toxic effect of A, in neuronal cultures that involves interaction with integrins, activation of FAK/src, enhanced phosphorylation of ERK1/2, and induction of the cell cycle, all leading to neuronal death. © 2007 Wiley-Liss, Inc. [source] An Integrin and Rho GTPase-Dependent Pinocytic Vacuole Mechanism Controls Capillary Lumen Formation in Collagen and Fibrin MatricesMICROCIRCULATION, Issue 1 2003GEORGE E. DAVIS ABSTRACT A major question that remains unanswered concerning endothelial cell (EC) morphogenesis is how lumens are formed in three-dimensional extracellular matrices (ECMs). Studies from many laboratories have revealed a critical role for an ECM-integrin-cytoskeletal signaling axis during EC morphogenesis. We have discovered a mechanism involving intracellular vacuole formation and coalescence that is required for lumen formation in several in vitro models of morphogenesis. In addition, a series of studies have observed vacuoles in vivo during angiogenic events. These vacuoles form through an integrin-dependent pinocytic mechanism in either collagen or fibrin matrices. In addition, we have shown that the Cdc42 and Rac1 guanosine triphosphatases (GTPases), which control actin and microtubule cytoskeletal networks, are required for vacuole and lumen formation. These GTPases are also known to regulate integrin signaling and are activated after integrin-matrix interactions. Furthermore, the expression of green fluorescent protein-Rac1 or -Cdc42 chimeric proteins in ECs results in the targeting of these fusion proteins to intracellular vacuole membranes during lumen formation. Thus, a matrix-integrin-cytoskeletal signaling axis involving both the Cdc42 and Rac1 GTPases regulates the process of EC lumen formation in three-dimensional collagen or fibrin matrices. [source] LIM domain-containing adaptor, leupaxin, localizes in focal adhesion and suppresses the integrin-induced tyrosine phosphorylation of paxillinCANCER SCIENCE, Issue 2 2010Toshiyuki Tanaka Focal adhesion (FA) consists of multiple cellular proteins including paxillin and serves as a center for adhesion-mediated signaling. The assembly and disassembly of FAs is regulated by locally produced intracellular signals, and tyrosine phosphorylation of paxillin has been implicated in this process. A Lin-11 Isl-1 Mec-3 (LIM) domain-containing adaptor protein, leupaxin, a member of the paxillin family, is expressed in leukocytes as well as in certain cancer cells, and shares overall structural characteristics with paxillin. However, it remains unknown whether leupaxin and paxillin cooperate with or antagonize each other in integrin signaling. Here we show that leupaxin potently represses the tyrosine phosphorylation of paxillin. When expressed in mouse thymoma BW5147 cells bound to ICAM-1, leupaxin accumulated in FA-like patches in the cell periphery. When expressed in NIH3T3 and HEK293T cells, leupaxin localized to FAs upon cell adhesion to fibronectin and strongly suppressed the integrin-induced tyrosine phosphorylation of paxillin. In integrin-stimulated HEK293T cells, leupaxin's LIM3 domain appeared essential for selective FA localization and the suppression of paxillin tyrosine phosphorylation. Leupaxin's LD3 motif, which is critical for stable association with FAK, was dispensable for leupaxin's suppressive ability. In addition, leupaxin reduced the spreading of NIH3T3 cells on fibronectin, which required both the LD3 motif and LIM3 domain. When expressed in human leukocytic K562 cells, leupaxin significantly suppressed integrin ,5,1-mediated cell adhesion to fibronectin and the tyrosine phosphorylation of paxillin. These findings indicate that leupaxin functions as a paxillin counterpart that potently suppresses the tyrosine phosphorylation of paxillin during integrin signaling. (Cancer Sci 2009) [source] | |||||||||||||