Analysis of FAK‐associated signaling pathways in the regulation of cell cycle progression

Reiske, Heinz; Zhao, Jihe; Han, Dong Cho; Cooper, Lee Ann; Guan, Jun‐Lin

doi:10.1016/s0014-5793(00)02295-x

Cited by 50 publications

(40 citation statements)

References 33 publications

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“…There are no reports which suggest a role for Grb7 in the regulation of cell proliferation. Indeed, our laboratory has shown recently that overexpression of the Grb7 SH2 domain does not decrease cell cycle progression (Reiske et al, 2000), although it inhibited cell migration under similar conditions (Han and Guan, 1999). These results suggest that Grb7 family members may play di erent roles in various cellular functions such as cell proliferation and migration.…”

Section: Roles In Cell Proliferation and Apoptosismentioning

confidence: 93%

The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions

2001

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Section: Roles In Cell Proliferation and Apoptosismentioning

confidence: 93%

The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions

2001

Self Cite

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“…FAK Phosphorylation-Recruitment of p125 FAK to focal contacts results in its activation through the phosphorylation of tyrosine residues (40). We compared the level of p125 FAK protein as well as its activity between Swiss 3T3 and LA1 cells.…”

Section: Mmp Inhibitors Promote P125mentioning

confidence: 99%

MMP Inhibitors Augment Fibroblast Adhesion through Stabilization of Focal Adhesion Contacts and Up-regulation of Cadherin Function

Ho¹,

Voura²,

Soloway³

et al. 2001

Journal of Biological Chemistry

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Increased pericellular proteolysis due to an imbalance between MMPs (matrix metalloproteinases) and TIMPs (tissue inhibitors of metalloproteinases) promotes early stages of tumorigenesis. We have reported that TIMP-1 down-regulation confers tumorigenicity on immortal Swiss 3T3 fibroblasts. In pursuit of the mechanism involved in this transformation, we asked whether MMP inhibitors modulate contact inhibition and cell adhesion, because the dysregulation of these events is essential for cellular transformation. Using both genetic and biochemical means, we demonstrate that MMP inhibitors regulate fibroblast cell adhesion. TIMP-1 down-regulated cells formed dense, multilayered colonies, suggesting a loss of contact inhibition. Recombinant TIMP-1 and synthetic MMP inhibitors (MMPi) restored normal cell contact and density of these cells in a dose-dependent manner. Consequently, the effect of MMPi on both cell-extracellular matrix (ECM) and cell-cell adhesion were investigated. Upon MMPi treatment, p125 FAK was redistributed, together with vinculin, to points of cell-ECM contact. Furthermore, phosphorylation of p125 FAK was restored to levels similar to that of wild type. In parallel, MMPi treatment increased cadherin levels and stabilized cadherin-mediated cell-cell contacts. Moreover, enhanced cadherin function was evident as increased calcium-dependent cell-cell aggregation and co-localization of cadherin and ␤-catenin at the cell membrane. We also obtained independent evidence of altered cadherin function using timp-1 ؊/؊ mouse embryonic fibroblasts. Our data provide provocative evidence that increased pericellular proteolysis impacts cell adhesion systems to offset normal contact inhibition, with subsequent effects on cell transformation and tumorigenesis. Matrix metalloproteinases (MMPs)1 and their tissue inhibitors (TIMPs) constitute a key system of pericellular proteolysis within the cell microenvironment. Our understanding of the role of this proteolytic system in cancer has evolved over the past decade. Initially linked to tumor invasion and metastasis, an MMP:TIMP imbalance is now thought to function in promoting early events of tumor development (1). The current emphasis is on identifying the mechanisms underlying these early effects. A better understanding of the relationship between MMP:TIMP activity and cell-extracellular matrix (ECM) and cell-cell communication is fundamental to this effort. We had reported that down-regulation of TIMP-1 expression caused an immortal fibroblast cell line to become tumorigenic (2). Extensive literature has since led to the knowledge that cancer involves a disrupted balance between MMPs and TIMPs. Both TIMPs and MMPs have been manipulated through genetic and biochemical approaches in tissue culture systems to demonstrate that, in general, TIMPs inhibit tumor cell invasion, angiogenesis, metastasis, and tumor formation (3-9), whereas MMPs promote these events (10 -13). Transgenic and knockout animals have further supported the role of this proteolytic system in early tumo...

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“…However, identification of the constituents of FAK signaling complexes that regulate proliferation and/or migration signals and the relative contributions of these distinct complexes toward these cellular processes is poorly understood and is an area of intense investigation. Recently, Reiske et al (2000) and Oktay et al (1999) reported that the formation of a FAK/Src complex and interaction with p130 CAS are required for the regulation of cell-cycle progression by FAK. Conversely, Xie et al (2001) have reported that FAK can associate with signal transducer and activator of transcription-1 (STAT-1) and that this signaling complex can promote cell migration.…”

Section: Antisense Targeting Of Fak Reduces Mmp2 Activitymentioning

confidence: 99%

“…FAK plays a key role in regulating cytoskeletal organization, gene expression, and cell behavior such as cell spreading and migration (Hanks and Polte, 1997). In addition, FAK may also have a role in regulating the G1 to S phase transition of the cell cycle (Reiske et al, 2000;Zhao et al, 1998) and the suppression of anoikis (Frisch et al, 1996;Hungerford et al, 1996;Ruoslahti and Reed, 1994;Xu et al, 1996).…”

mentioning

confidence: 99%

Focal Adhesion Kinase Is a Key Mediator of Human Trophoblast Development

MacPhee

Mostachfi

Han

et al. 2001

Laboratory Investigation

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SUMMARY:Trophoblast differentiation during the first trimester of pregnancy involves cell proliferation and invasion and extracellular matrix (ECM) remodeling. Reports have indicated that, in a variety of cell types, processes such as proliferation, invasion, and ECM remodeling require the turnover of focal adhesions mediated by a cytoplasmic tyrosine kinase named focal adhesion kinase (FAK). Therefore, in the present study we examined the expression and spatial localization of FAK during early human placental development. Immunocytochemical and immunoblot analysis showed that FAK and a focal adhesionassociated protein named paxillin were highly expressed between the 5th and 8th weeks of gestation, specifically in villous cytotrophoblast and extravillous trophoblast (EVT) cells. Activated FAK, phosphorylated on Tyr-397, colocalized with ␣5 integrin and matrix metalloproteinase-2 (MMP2) expression in EVT cells within a previously characterized intermediate, invasiverestrained region. FAK and paxillin expression dramatically decreased after 10 to 12 weeks of gestation coincident with increasing pO 2 levels. Exposure of human villous explants of 5 to 8 weeks to a 3% O 2 environment resulted in increased trophoblast outgrowth, cell proliferation, and detection of ␣5 integrin and MMP2, as well as increased activation of FAK in EVT cells compared with explants grown in a 20% O 2 environment. To determine whether FAK was a key requisite for trophoblast differentiation, villous explants of 5 weeks gestation were grown in Matrigel in a 3% O 2 environment and incubated with 20-mer antisense FAK oligonucleotides. A dramatic reduction of trophoblast outgrowth was observed in antisense-treated explants compared with missense and control cultures, and, in addition, cell proliferation and MMP2 activity in antisense-treated explants were dramatically reduced. These data suggest that FAK is a key kinase involved in early trophoblast cell differentiation and plays a role in regulating cell proliferation and motility during early placental development. (Lab Invest 2001, 81:1469 -1483.

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Analysis of FAK‐associated signaling pathways in the regulation of cell cycle progression

Cited by 50 publications

References 33 publications

The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions

The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions

MMP Inhibitors Augment Fibroblast Adhesion through Stabilization of Focal Adhesion Contacts and Up-regulation of Cadherin Function

Focal Adhesion Kinase Is a Key Mediator of Human Trophoblast Development

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