FAK promotes organization of fibronectin matrix and fibrillar adhesions

Ilić, Duško; Kovačič, Branka; Johkura, Kohei; Schlaepfer, David D.; Tomašević, Nenad; Han, Qin; Kim, Jae Beom; Howerton, Kyle; Baumbusch, Clark; Ogiwara, Naoko; Streblow, Daniel N.; Nelson, Jay A.; Dazin, Paul; Shino, Yuji; Sasaki, Katsunori; Damsky, Caroline H.

doi:10.1242/jcs.00845

Cited by 114 publications

(103 citation statements)

References 41 publications

(39 reference statements)

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“…FAK is a critical regulator of FN matrix assembly as FAK-null cells do not assemble an FN matrix (59). We found that phosphorylation on FAK Tyr-397 was significantly higher in cells on a rigid substrate after 2 h compared with those on a soft substrate.…”

Section: Gј Ementioning

confidence: 73%

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

Carraher

Schwarzbauer

2013

Journal of Biological Chemistry

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Background: Cell behavior is affected by changes in extracellular matrix stiffness during disease progression. Results: Fibronectin matrix assembly is inhibited on soft substrates but can be restored by manipulating cell-fibronectin binding or by partially unfolding substrate fibronectin. Conclusion: On soft substrates, cells are deficient in integrin-fibronectin bond strength and therefore cannot induce fibronectin conformational changes required for assembly. Significance: Rigidity-dependent changes in fibronectin conformation provide a novel mechanism for mechanotransduction.

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Section: Gј Ementioning

confidence: 73%

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

Carraher

Schwarzbauer

2013

Journal of Biological Chemistry

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“…The compact conformation of FN dimers is maintained by intramolecular interactions involving the type III 12-14 repeats of FN. 53,54 The type III [12][13][14] repeats, also known as heparin II binding domain, interact with the HS chains from various members of the Sdc family. 55 Binding of Sdc1 with heparin II may facilitate unfolding of dimeric FNs and expose FN self-assembly (FN-binding) sites, thus promoting FN deposition and fibrillogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Concomitant engagement of Sdc4 and integrins promotes Rho GTPase and focal adhesion kinase (FAK) activities, which are crucial for efficient initiation of FN matrix assembly. [12][13][14][15] Sdc1 is expressed primarily by epithelial and plasma cells of healthy adult tissue. 16 Recently, we and others 17,18 observed the induction of Sdc1 in stromal fibroblasts of invasive breast carcinomas.…”

mentioning

confidence: 99%

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

Yang

Mosher

Seo

et al. 2011

The American Journal of Pathology

123

126

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Stromal fibroblasts of breast carcinomas frequently express the cell surface proteoglycan syndecan-1 (Sdc1). In human breast carcinoma samples, stromal Sdc1 expression correlates with an organized, parallel, extracellular matrix (ECM) fiber architecture. To examine a possible link between stromal Sdc1 and the fiber architecture, we generated bioactive cell-free three-dimensional ECMs from cultures of Sdc1-positive and Sdc1-negative murine and human mammary fibroblasts (termed ECM-Sdc1 and ECM-mock, respectively). Indeed, ECM-Sdc1 showed a parallel fiber architecture that contrasted markedly with the random fiber arrangement of ECM-mock. When breast carcinoma cells were seeded into the fibroblast-free ECMs, ECM-Sdc1, but not ECM-mock, promoted their attachment, invasion, and directional movement. We further evaluated the contribution of the structural/compositional modifications in ECM-Sdc1 on carcinoma cell behavior. By microcontact printing of culture surfaces, we forced the Sdc1-negative fibroblasts to produce ECM with parallel fiber organization, mimicking the architecture observed in ECM-Sdc1. We found that the fiber topography governs carcinoma cell migration directionality. Conversely, an elevated fibronectin level in ECM-Sdc1 was responsible for the enhanced attachment of the breast carcinoma cells. These observations suggest that Sdc1 expression in breast carcinoma stromal fibroblasts promotes the assembly of an architecturally abnormal ECM that is permissive to breast carcinoma directional migration and invasion. Epithelial-stromal interactions play crucial roles in directing mammary gland development and in maintaining normal tissue homeostasis. Conversely, during tumorigenesis, the stroma accelerates carcinoma growth and progression. The predominant cell type within the stromal compartment is the fibroblast, which synthesizes, organizes, and maintains a three-dimensional (3D) network of glycoproteins and proteoglycans known as the extracellular matrix (ECM). Normal stromal fibroblasts and their ECM are believed to exert an inhibitory constraint on tumor growth and progression. 1,2 Major alterations occur in the stromal fibroblasts and ECM during neoplastic transformation, giving rise to a permissive and supportive microenvironment for carcinomas. Compared with their quiescent normal counterpart, carcinoma-associated fibroblasts display an activated phenotype, which is characterized by the expression of smooth muscle markers, an enhanced proliferative and migratory potential, and altered gene expression profiles. Carcinoma-associated fibroblasts produce and deposit elevated amounts and abnormal varieties of ECM components. 3-5 Recent evidence 6,7 indicates that not only ECM composition but also ECM architecture are altered in carcinomas and that these changes may promote tumor progression. However, the contribution of these stromal modifications to tumor development and the molecular mechanisms and signaling events underlying these alterations are incompletely understood.

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“…Interestingly, fakÀ/À fibroblasts similarly exhibit a defect in fibronectin matrix assembly (Ilic et al, 2004). This defect can be rescued by re-expression of wild-type FAK, but not by FAK397F, nor by a FAK mutant that is impaired for binding p130 CAS (Ilic et al, 2004). Together these findings suggest that the FAK/SFK complex may be the active signaling component promoting assembly of the fibronectin matrix and that p130 CAS may be an important downstream effector for this function.…”

Section: Role Of Src Kinases In the Assembly Of Fibronectin Matrixmentioning

confidence: 92%

“…Second, pharmacological inhibition of Src family kinases also impairs the assembly of a fibronectin matrix (Wierzbicka-Patynowski and Schwarzbauer, 2002). Interestingly, fakÀ/À fibroblasts similarly exhibit a defect in fibronectin matrix assembly (Ilic et al, 2004). This defect can be rescued by re-expression of wild-type FAK, but not by FAK397F, nor by a FAK mutant that is impaired for binding p130 CAS (Ilic et al, 2004).…”

Section: Role Of Src Kinases In the Assembly Of Fibronectin Matrixmentioning

confidence: 99%

The interplay between Src and integrins in normal and tumor biology

2004

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Src family nonreceptor protein tyrosine kinases transduce signals that control normal cellular processes such as cell proliferation, adhesion and motility. Normally, cellular Src is held in an inactive state, but in several cancer types, abnormal events lead to elevated kinase activity of the protein and cause pleiotropic cellular responses inducing transformation and metastasis. A prerequisite of the ability of a cancer cell to undergo metastasis into distant tissues is to penetrate surrounding extracellular matrices. These processes are facilitated by the integrin family of cell adhesion molecules. As is the case with Src, altered integrin activity or substrate affinity can contribute to the neoplastic phenotype. Therefore, understanding the interplay between Src and integrin function has been of intense interest over the past few years. This review focuses on the role of Src and integrin signaling in normal cells and how this is deregulated in human cancer. We will identify the key players in the integrin-mediated signaling pathways involved in cell motility and apoptosis, such as FAK, paxillin and p130 CAS , and discuss how Src signaling affects the formation of focal adhesions and the extracellular matrix.

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FAK promotes organization of fibronectin matrix and fibrillar adhesions

Cited by 114 publications

References 41 publications

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

Regulation of Matrix Assembly through Rigidity-dependent Fibronectin Conformational Changes

Syndecan-1 in Breast Cancer Stroma Fibroblasts Regulates Extracellular Matrix Fiber Organization and Carcinoma Cell Motility

The interplay between Src and integrins in normal and tumor biology

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