Focal Adhesions: A Nexus for Intracellular Signaling and Cytoskeletal Dynamics

Sastry, Sarita K.; Burridge, Keith

doi:10.1006/excr.2000.5043

Cited by 473 publications

(348 citation statements)

References 111 publications

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“…One of the major transducers of ECM/integrinderived signals is the focal adhesion kinase (FAK), a 125-kDa nonreceptor tyrosine kinase that can bind to, and phosphorylate, a number of intracellular signaling molecules, including Src, paxillin and p130cas, and mediate downstream activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling through a network of adaptor proteins (reviewed in Boudreau andJones, 1999 andSastry andBurridge, 2000). Increased FAK expression and/or activation have been documented in various malignancies and shown to correlate with the invasive/metastatic phenotypes of the cells (reviewed in Gabarra-Niecko et al, 2003 andKahana et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27 IGFÀIR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen a1 and a2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/a2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by smallinterfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

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Section: Introductionmentioning

confidence: 99%

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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“…During the process, not only do cells undergo morphogenesis but they also remodel the matrix components. The general dogma is that a chemical 1 or mechanical 2 stimulus signaled through focal adhesion points 3 changes the polymerization state of the cytoskeletal actin and subsequent cellular activity. 4 A complex cascades of events follow including the activation of intracellular signaling pathways with tyrosine phosphorylation of focal adhesion kinases (FAKs) that change the differentiation, proliferation and migration of cells.…”

Section: Introductionmentioning

confidence: 99%

Cell colonization in degradable 3D porous matrices

Lawrence

Madihally

2008

Cell Adhesion & Migration

178

155

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Cell colonization is an important in a wide variety of biological processes and applications including vascularization, wound healing, tissue engineering, stem cell differentiation and biosensors. During colonization porous 3D structures are used to support and guide the ingrowth of cells into the matrix. In this review, we summarize our understanding of various factors affecting cell colonization in three-dimensional environment. The structural, biological and degradation properties of the matrix all play key roles during colonization. Further, specific scaffold properties such as porosity, pore size, fiber thickness, topography and scaffold stiffness as well as important cell material interactions such as cell adhesion and mechanotransduction also influence colonization.

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“…Cell attachment, spreading, and motility are complex processes requiring the integration of diverse signaling networks and structural assemblies (Jockusch et al, 1995;Sastry and Burridge, 2000;Juliano, 2002). One of the earliest steps in transducing extracellular cues through integrins to the cytoskeleton is the activation of the tyrosine kinases Src and FAK (Schwartz et al, 1995;Giancotti and Tarone, 2003).…”

Section: Introductionmentioning

confidence: 99%

Src and FAK Kinases Cooperate to Phosphorylate Paxillin Kinase Linker, Stimulate Its Focal Adhesion Localization, and Regulate Cell Spreading and Protrusiveness

Brown

Cary

Jamieson

et al. 2005

MBoC

167

179

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The ArfGAP paxillin kinase linker (PKL)/G protein-coupled receptor kinase-interacting protein (GIT)2 has been implicated in regulating cell spreading and motility through its transient recruitment of the p21-activated kinase (PAK) to focal adhesions. The Nck-PAK-PIX-PKL protein complex is recruited to focal adhesions by paxillin upon integrin engagement and Rac activation. In this report, we identify tyrosine-phosphorylated PKL as a protein that associates with the SH3-SH2 adaptor Nck, in a Src-dependent manner, after cell adhesion to fibronectin. Both cell adhesion and Rac activation stimulated PKL tyrosine phosphorylation. PKL is phosphorylated on tyrosine residues 286/392/592 by Src and/or FAK and these sites are required for PKL localization to focal adhesions and for paxillin binding. The absence of either FAK or Src-family kinases prevents PKL phosphorylation and suppresses localization of PKL but not GIT1 to focal adhesions after Rac activation. Expression of an activated FAK mutant in the absence of Src-family kinases partially restores PKL localization, suggesting that Src activation of FAK is required for PKL phosphorylation and localization. Overexpression of the nonphosphorylated GFP-PKL Triple YF mutant stimulates cell spreading and protrusiveness, similar to overexpression of a paxillin mutant that does not bind PKL, suggesting that failure to recruit PKL to focal adhesions interferes with normal cell spreading and motility. INTRODUCTIONCell attachment, spreading, and motility are complex processes requiring the integration of diverse signaling networks and structural assemblies (Jockusch et al., 1995;Sastry and Burridge, 2000;Juliano, 2002). One of the earliest steps in transducing extracellular cues through integrins to the cytoskeleton is the activation of the tyrosine kinases Src and FAK (Schwartz et al., 1995;Giancotti and Tarone, 2003). FAK is an integrin-binding nonreceptor tyrosine kinase that upon integrin ligation is activated to autophosphorylate Y397 and bind to the Src SH2 domain (Schaller et al., 1994;Calalb et al., 1995). Src then phosphorylates FAK on multiple residues that increase FAK kinase activity and several downstream binding partners for Src/FAK are targeted for phosphorylation, including the focal adhesion proteins p130Cas and paxillin (reviewed in Brown and Turner, 2004;Playford and Schaller, 2004;Mitra et al., 2005). Phosphorylated paxillin binding to the SH2/SH3 adaptor protein Crk is implicated in Rac activation and stimulation of cell motility (Petit et al., 2000;Lamorte et al., 2003;Valles et al., 2004), whereas binding of paxillin to the p120RasGAP SH2 domain may displace and allow for the activation of p190RhoGAP and subsequent decrease in RhoA activity (Iwasaki et al., 2002).The Cdc42, Rac1, and RhoA members of the Ras superfamily of p21 GTPases are central intermediaries in coordinating the defined temporal-spatial progression of signals emanating from initial integrin ligation, through acquisition of a polarized state, to initiation and maintenance of directed ce...

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Focal Adhesions: A Nexus for Intracellular Signaling and Cytoskeletal Dynamics

Cited by 473 publications

References 111 publications

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Cell colonization in degradable 3D porous matrices

Src and FAK Kinases Cooperate to Phosphorylate Paxillin Kinase Linker, Stimulate Its Focal Adhesion Localization, and Regulate Cell Spreading and Protrusiveness

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