Focal adhesion kinase promotes phospholipase C-γ1 activity

Zhang, Xiaoe; Chattopadhyay, Ansuman; Ji, Qunsheng; Owen, James D.; Ruest, Paul J.; Carpenter, Graham; Hanks, Steven K.

doi:10.1073/pnas.96.16.9021

Cited by 162 publications

(143 citation statements)

References 56 publications

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Section: Discussionmentioning

confidence: 99%

“…It is particularly significant that Y397 is the responding site because this site is central to the formation of complexes based on the binding of SH2 domains to its phosphorylated form. The SH2 domains of src, PI3-kinase, PLC␥, Grb7, and Shc have been reported to bind pY397 providing many potential downstream signaling consequences (Schaller et , 1994;Schlaepfer and Hunter, 1997;Han and Guan, 1999;Reiske et al, 1999;Zhang et al, 1999).Most current integrin signaling data has been interpreted in the context of the integrin-clustering model. The plating of fibroblasts on a fibronectin-coated surface induces not only the binding of ␣5␤1 to fibronectin, but also the progressive organization of ␣5␤1 into focal contacts and focal adhesions during the process of cell spreading (Singer et al, 1988;Pankov et al, 2000).…”

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confidence: 99%

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A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

Shi

Boettiger

2003

MBoC

133

113

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The common model for integrin mediated signaling is based on integrin clustering and the potential for that clustering to recruit signaling molecules including FAK and src. The clustering model for transmembrane signaling originated with the analysis of the EGF receptor signaling and remains the predominant model. The roles for substrate-bound ligand and ligand occupancy in integrin-mediated signaling are less clear. A kinetic model was established using HT1080 cells in which there was a linear relationship between the strength of adhesion, the proportion of ␣5␤1 integrin that could be chemically cross-linked, and the number of receptor-ligand bonds. This graded signal produced a similarly graded response measured by the level of specific phosphorylation of FAK Y397. FAK Y397 phosphorylation could also be induced by antibody bound to the substrate. In contrast, clustering of ␣5␤1 on suspended cells with either antibody to ␤1 or by clustering of soluble ligand bound to ␣5␤1 induced the phosphorylation of FAK Y861 but not Y397. There were no differences in signaling when activating antibodies were compared with blocking antibodies, presence or absence of ligand. Only tethering of ␣5␤1 to the substrate was required for induction of FAK Y397 phosphorylation. INTRODUCTIONThere are several classes of transmembrane receptors that are involved in the transmission of signals from the extracellular space across the plasma membrane. It is a logical requirement of these systems that ligand binding to the extracellular domain results in a change in the cytoplasmic domain. How the signal is transferred from the extracellular domain is basic to the generation of the intracellular downstream signals. Allosteric proteins have been described in which the occupation of a binding site on one side of the protein can result in a conformational change that affects other binding sites. The interposition of a lipid bilayer between the receiving and effector domains of the transmembrane receptors poses limitations in the application of the allosteric model. Although a few of the receptor tyrosine kinase receptor systems have been analyzed in detail, the mechanism for transmembrane signal transduction by other receptor classes is less well understood.The EGF receptor is the best understood model. Receptor dimerization is initiated by the binding of EGF to extracellular domain 1 altering the conformation of the extracellular domain to generate a dimerization of receptors mediated through domain 2. This dimerization brings the cytoplasmic domains of two EGF receptors into proximity and allows the cross-phosphorylation of cytoplasmic domains by the encoded tyrosine kinase (Schlessinger, 2000). The generation of signals through receptor dimerization is a general theme. Among the tyrosine kinase receptors the mechanisms of generating the dimer vary from the use of bivalent ligands for growth hormone and erythropoietin (Kossiakoff and de Vos, 1998;Jiang and Hunter, 1999), to dimeric ligands for PDGF and VEGF (Wiesmann et al., 1997), to complexe...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

Shi

Boettiger

2003

MBoC

133

113

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“…The genes coding for cmyc epiotope-tagged FAK and FAK Y397F were PCR-amplified from the pRC/CMV-c-myc FAK expression plasmids kindly provided by Dr. Steven K. Hanks [44] and ligated into the pMSCVneo expression vector as restriction fragments at the HpaI-to-BglII site. The mouse fibroblast retroviral packaging cell line, PT67, was transfected with the pMSCVneo/c-myc-FAK plasmids using the TransIT-3T3 transfection kit purchased from Mirus Corp. (Madison, WI).…”

Section: Retrovirus Construction and Hmsc Transductionmentioning

confidence: 99%

Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells

Salasznyk

Klees

Williams

et al. 2007

Experimental Cell Research

265

225

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The intracellular signaling events controlling human mesenchymal stem cell (hMSC) differentiation into osteoblasts are not entirely understood. We recently demonstrated that contact with extracellular matrix (ECM) proteins is sufficient to induce osteogenic differentiation of hMSC through an ERKdependent pathway. We hypothesized that FAK signaling pathways provide a link between activation of ERK 1/2 by ECM, and stimulate subsequent phosphorylation of the Runx2/Cbfa-1 transcription factor that controls osteogenic gene expression. We plated hMSC on purified collagen I (COLL-I) and vitronectin (VN) in the presence or absence of FAK-specific siRNA, and assayed for phosphorylation of Runx2/Cbfa-1 as well as expression of established osteogenic differentiation markers (bone sialoprotein-2, osteocalcin, alkaline phosphatase, calcium deposition, and spectroscopically determined mineral:matrix ratio). We found that siRNA treatment reduced FAK mRNA levels by >40% and decreased ECM-mediated phosphorylation of FAK Y397 and ERK 1/2. Serine phosphorylation of Runx2/Cbfa-1 was significantly reduced after 8 days in treated cells. Finally, FAK inhibition blocked osterix transcriptional activity and the osteogenic differentiation of hMSC, as assessed by lowered expression of osteogenic genes (RT-PCR), decreased alkaline phosphatase activity, greatly reduced calcium deposition, and a lower mineral:matrix ratio after 28 days in culture. These results suggest that FAK signaling plays an important role in regulating ECMinduced osteogenic differentiation of hMSC.

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“…The N-terminal SH2 domain of PLC-γ1 is known to play a major role in the association with the activated growth factor receptor, while the C-terminal SH2 domain is considered to play a minor role (Chattopadyay et al, 1999;Poulin et al, 2000). However, recently, it has been reported that the C-terminal SH2 domain of PLC-γ1 is involved in interactions with synaptojanin (Ahn et al, 1998), the actin-cytoskeleton (Pei et al, 1996), PIP 3 (Bae et al, 1998;Rameh et al, 1998) and FAK (Zhang et al, 1999). These observations suggest that the two SH2 domains of PLC-γ1 are dissimilar and may mediate the recognition of specific phosphorylation sites.…”

Section: Activation Of Plc-γ γ γ γ1mentioning

confidence: 99%

The mechanism of phospholipase C-γ1 regulation

Kim

Kim²,

Ryu³

et al. 2000

Exp Mol Med

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OverviewPhospholipase C (PLC) 1 hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate the second messengers, inositol 1,4,5-trisphosphate (IP 3 ) and diacylglycerol (DAG). IP 3 induces a transient increase in intracellular free Ca 2+ , while DAG directly activates protein kinase C. Upon stimulation of cells with growth factors, PLC-γ γ γ γ1 is activated upon their association with and phosphorylation by receptor and non-receptor tyrosine kinases. In this review, we will focus on the activation mechanism and regulatory function of PLC-γ γ γ γ1.Keywords: phospholipase C, protein kinase C IntroductionPhosphoinositide-specific phospholipase C (PLC) plays a pivotal role in transmembrane signaling. In response to various extracellular stimuli, such as hormones, growth factors, and neurotransmitters, PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2 ) producing two second messengers, diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP 3 ). IP 3 induces a transient increase in intracellular free Ca 2+ , while DAG is a direct activator of protein kinase C (PKC) (Nishizuka, 1986;Berridge and Irvine, 1989). These processes have been implicated in many cellular physiological functions, such as secretion, cell proliferation, cell growth and differentiation (Rana and Hokin, 1990). In spite of low overall homology in the predicted amino acid sequences of the multiple PLCisozymes, there are significant sequence similarities in two domains which are designated as the X-and Ydomain (Noh et al., 1995;Rhee and Bae, 1997; Sekiyama et al., 1999). So far, ten mammalian PLC-isozymes have been characterized at the cDNA level; they can be subdivided into three types (β, γ, δ) on the basis of relative locations of the X-and Y-domains in the primary structure (Noh et al., 1995;Rhee and Bae, 1997). The β type includes four PLCs (PLC-β1 through PLC-β4), the γ type includes two PLCs (PLC-γ1 and PLC-γ2), and the δ type includes four enzymes (PLC-δ1 through PLC-δ4) (Suh et al., 1988;Noh et al., 1995;Rhee and Bae, 1997) ( Figure 1). The existence of multiple forms of PLC enzymes suggests that each isozyme may differ in some respect, in tissue distribution, intracellular localization, regulatory mechanisms, and other downstream functions. Emerging evidence suggests that an additional level of diversity may exist beyond the above subgroup classification, because individual genes may yield multiple PLC products due to alternative splicing of the mRNA (Bahk et al., 1994;Kim et al., 1998). The diversity among the PLC enzymes point to selective coupling of individual PLCs to different receptors and signaling pathways. However, very little is known about the identity of the specific signaling pathways for each isozymes or how each isozymes function in vivo. Although PLC enzymes have been purified and extensively characterized biochemically, their function in vivo remains to be clarified.The catalytic activities of the PLC-β type isozymes in vivo are mediated by α-and βγ subunits of heterotrimeric G-proteins (Smrcka et al., 1991;...

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Focal adhesion kinase promotes phospholipase C-γ1 activity

Cited by 162 publications

References 56 publications

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

A Novel Mode for Integrin-mediated Signaling: Tethering Is Required for Phosphorylation of FAK Y397

Focal adhesion kinase signaling pathways regulate the osteogenic differentiation of human mesenchymal stem cells

The mechanism of phospholipase C-γ1 regulation

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