scholarly journals Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms

2006 ◽  
Vol 26 (11) ◽  
pp. 4201-4213 ◽  
Author(s):  
Patrick Bryant ◽  
Qingxia Zheng ◽  
Kevin Pumiglia
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Kinase Inhibitors ◽  
Critical Role ◽  
Dominant Negative ◽  
Regulatory Control ◽  
Endothelial Cell Proliferation ◽  
F Box Protein

ABSTRACT Endothelial cell proliferation is a critical step in angiogenesis and requires a coordinated response to soluble growth factors and the extracellular matrix. As focal adhesion kinase (FAK) integrates signals from both adhesion events and growth factor stimulation, we investigated its role in endothelial cell proliferation. Expression of a dominant-negative FAK protein, FAK-related nonkinase (FRNK), impaired phosphorylation of FAK and blocked DNA synthesis in response to multiple angiogenic stimuli. These results coincided with elevated cyclin-dependent kinase inhibitors (CDKIs) p21/Cip and p27/Kip, as a consequence of impaired degradation. FRNK inhibited the expression of Skp2, an F-box protein that targets CDKIs, by inhibiting mitogen-induced mRNA. The FAK-regulated degradation of p27/Kip was Skp2 dependent, while levels of p21/Cip were regulated independent of Skp2. Skp2 is required for endothelial cell proliferation as a consequence of degrading p27. Finally, knockdown of both p21 and p27 in FRNK-expressing cells completely restored mitogen-induced endothelial cell proliferation. These data demonstrate a critical role for FAK in the regulation of CDKIs through two independent mechanisms: Skp2 dependent and Skp2 independent. They also provide important insights into the requirement of focal adhesion kinase for normal vascular development and reveal novel regulatory control points for angiogenesis.

scholarly journals Cordycepin Suppresses Endothelial Cell Proliferation, Migration, Angiogenesis, and Tumor Growth by Regulating Focal Adhesion Kinase and p53

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 168 ◽  
Author(s):  
Yi-Ting Lin ◽  
Shu-Man Liang ◽  
Ya-Ju Wu ◽  
Yi-Ju Wu ◽  
Yi-Jhu Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Tumor Growth ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Epithelial Mesenchymal Transition ◽  
Endothelial Cell Proliferation ◽  
Mice Model ◽  
Mesenchymal Transition

Focal adhesion kinase (FAK) plays an important role in vascular development, including the regulation of endothelial cell (EC) adhesion, migration, proliferation, and survival. 3’-deoxyadenosine (cordycepin) is known to suppress FAK expression, cell migration, and the epithelial–mesenchymal transition in hepatocellular carcinoma (HCC). However, whether cordycepin affects FAK expression and cellular functions in ECs and the specific molecular mechanism remain unclear. In this study, we found that cordycepin suppressed FAK expression and the phosphorylation of FAK (p-FAK) at Tyr397 in ECs. Cordycepin inhibited the proliferation, wound healing, transwell migration, and tube formation of ECs. Confocal microscopy revealed that cordycepin significantly reduced FAK expression and decreased focal adhesion number of ECs. The suppressed expression of FAK was accompanied by induced p53 and p21 expression in ECs. Finally, we demonstrated that cordycepin suppressed angiogenesis in an in vivo angiogenesis assay and reduced HCC tumor growth in a xenograft nude mice model. Our study indicated that cordycepin could attenuate cell proliferation and migration and may result in the impairment of the angiogenesis process and tumor growth via downregulation of FAK and induction of p53 and p21 in ECs. Therefore, cordycepin may be used as a potential adjuvant for cancer therapy.

scholarly journals PTP-ε, a tyrosine phosphatase expressed in endothelium, negatively regulates endothelial cell proliferation

2001 ◽  
Vol 281 (1) ◽  
pp. H396-H403 ◽  
Author(s):  
Larry J. Thompson ◽  
Jihong Jiang ◽  
Nageswara Madamanchi ◽  
Marschall S. Runge ◽  
Cam Patterson
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Umbilical Vein ◽  
Tyrosine Phosphatase ◽  
Critical Role ◽  
Functional Characterization ◽  
Endothelial Cell Proliferation ◽  
Vascular Events ◽  
Protein Tyrosine

The vascular endothelium is a dynamic interface between the blood vessel and circulating factors and, as such, plays a critical role in vascular events like inflammation, angiogenesis, and hemostasis. Whereas specific protein tyrosine kinases have been identified in these processes, less is known about their protein tyrosine phosphatase (PTP) counterparts. We utilized a RT-PCR/differential hybridization assay to identify PTP-ε as a highly abundant endothelial cell PTP. PTP-ε mRNA expression is growth factor responsive, suggesting a role for this enzyme in endothelial cell proliferation. Overexpression of PTP-ε decreases proliferation by 60% in human umbilical vein endothelial cells (HUVEC) but not in smooth muscle cells or fibroblasts. In contrast, overexpression of PTP-ε (D284A), a catalytically inactive mutant, has no significant effect on HUVEC proliferation. These data provide the first functional characterization of PTP-ε in endothelial cells and identify a novel pathway that negatively regulates endothelial cell growth. Such a pathway may have important implications in vascular development and angiogenesis.

scholarly journals v-Crk Activates the Phosphoinositide 3-Kinase/AKT Pathway by Utilizing Focal Adhesion Kinase and H-Ras

2002 ◽  
Vol 22 (20) ◽  
pp. 7015-7023 ◽  
Author(s):  
Tsuyoshi Akagi ◽  
Kazutaka Murata ◽  
Tomoyuki Shishido ◽  
Hidesaburo Hanafusa
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Critical Role ◽  
Sh3 Domain ◽  
Sh2 Domain ◽  
Dominant Negative ◽  
Regulatory Subunit ◽  
Akt Pathway ◽  
Dominant Negative Mutant ◽  
Phosphoinositide 3 Kinase

ABSTRACT v-Crk, an oncogene product of avian sarcoma virus CT10, efficiently transforms chicken embryo fibroblasts (CEF). We have recently reported that constitutive activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway plays a critical role in the v-Crk-induced transformation of CEF. In the present study we investigated the molecular mechanism by which v-Crk activates the PI3K/AKT pathway. First, we found that v-Crk promotes the association of the p85 regulatory subunit of PI3K with focal adhesion kinase (FAK) by inducing the phosphorylation of the Y397 residue in FAK. This FAK phosphorylation needs activation of the Src family tyrosine kinase(s) for which the v-Crk SH2 domain is responsible. v-Crk was unable to activate the PI3K/AKT pathway in FAK-null cells, indicating the functional importance of FAK. In addition, we found that H-Ras is also required for the activation of the PI3K/AKT pathway. The v-Crk-induced activation of AKT was greatly enhanced by the overexpression of H-Ras or its guanine nucleotide exchange factor mSOS, which binds to the v-Crk SH3 domain, whereas a dominant-negative mutant of H-Ras almost completely suppressed this activation. Furthermore, we showed that v-Crk stimulates the interaction of H-Ras with the Ras binding domain in the PI3K p110 catalytic subunit. Our data indicated that the v-Crk-induced activation of PI3K/AKT pathway was cooperatively achieved by two distinct interactions. One is the interaction of p85 with tyrosine-phosphorylated FAK promoted by the v-Crk SH2 domain, and another is the interaction of p110 with H-Ras dictated by the v-Crk SH3 domain.

scholarly journals Identification of Kinases Activated by Multiple Pro-Angiogenic Growth Factors

2021 ◽  
Author(s):  
Jonathan Scott Gruver ◽  
Scott Rata ◽  
Leonid Peshkin ◽  
Marc W Kirschner
Keyword(s):  
Cell Proliferation ◽  
Growth Factors ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Growth Factor Receptors ◽  
Endothelial Cell Proliferation ◽  
Angiogenic Growth Factors

Antiangiogenic therapy began as an effort to inhibit VEGF signaling, which was thought to be the sole factor driving tumor angiogenesis. It has become clear that there are more pro-angiogenic growth factors that can substitute for VEGF during tumor vascularization. This has led to the development of multi-kinase inhibitors which simultaneously target multiple growth factor receptors. These inhibitors perform better than monotherapies yet to date no multi-kinase inhibitor targets all receptors known to be involved in pro-angiogenic signaling and resistance inevitably occurs. Given the large number of pro-angiogenic growth factors identified, it may be impossible to simultaneously target all pro-angiogenic growth factor receptors. Here we search for kinase targets, some which may be intracellularly localized, that are critical in endothelial cell proliferation irrespective of the growth factor used. We develop a quantitative endothelial cell proliferation assay and combine it with "kinome regression" or KIR, a recently developed method capable of identifying kinases that influence a quantitative phenotype. We report the kinases implicated by KIR and provide orthogonal evidence of their importance in endothelial cell proliferation. Our approach points to a new strategy to develop a more complete anti-angiogenic blockade.

Angiogenesis in the primate ovary

2001 ◽  
Vol 13 (8) ◽  
pp. 557 ◽  
Author(s):  
Hamish M. Fraser ◽  
Christine Wulff
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Corpus Luteum ◽  
Expression Patterns ◽  
Critical Role ◽  
Angiogenic Factor ◽  
Endothelial Cell Proliferation ◽  
Cell Proliferation Inhibition ◽  
Cyclic Changes

The ovary is distinctive in undergoing cyclic changes in angiogenesis that play a critical role in the normal functioning of the female reproductive system. The current paper describes the use of the marmoset monkey as an in vivo model in which the cellular and molecular regulation of angiogenesis in the ovary can be investigated and the effects of manipulation of angiogenic factors elucidated. The studies are based on quantifying changes in blood vessel area and endothelial cell proliferation, monitoring changes in expression patterns of putative angiogenic regulatory factors and targeting these factors by antagonists in vivo. Quantification of endothelial cell proliferation shows that angiogenesis commences in the pre-antral follicle, increases with follicular development and becomes intense in the early corpus luteum. Vascular endothelial growth factor (VEGF), a principal angiogenic factor, is synthesized by the developing follicle and corpus luteum. Administration of specific antagonists in vivo for selected periods of the ovulatory cycle shows that inhibition of VEGF results in a marked decrease in endothelial cell proliferation in the follicle and is accompanied by a decline in granulosa cell proliferation. Inhibition during the early or mid-luteal phase results in a marked suppression in luteal angiogenesis, failure of development of the microvascular tree and suppression of luteal function. Manipulation of angiogenesis should be a novel approach to either promoting or inhibiting the normal processes of folliculogenesis, ovulation and corpus luteum function.

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