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The Effect of Differentiation Induction on FAK and Src Activity in Live HMSCs Visualized by FRET  [PDF]
Xiaoling Liao, Shaoying Lu, Yiqian Wu, Wenfeng Xu, Yue Zhuo, Qin Peng, Bo Li, Ling Zhang, Yingxiao Wang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072233
Abstract: FAK and Src signaling play important roles in cell differentiation, survival and migration. However, it remains unclear how FAK and Src activities are regulated at the initial stage of stem cell differentiation. We utilized fluorescence resonance energy transfer (FRET)-based FAK and Src biosensors to visualize these kinase activities at the plasma membrane of human mesenchymal stem cells (HMSCs) under the stimulation of osteogenic, myoblastic, or neural induction reagents. Our results indicate that the membrane FAK and Src activities are distinctively regulated by these differentiation induction reagents. FAK and Src activities were both up-regulated with positive feedback upon osteogenic induction, while myoblastic induction only activated Src, but not FAK. Neural induction, however, transiently activated FAK and subsequently Src, which triggered a negative feedback to partially inhibit FAK activity. These results unravel distinct regulation mechanisms of FAK and Src activities during HMSC fate decision, which should advance our understanding of stem cell differentiation in tissue engineering.
Visualization of Src and FAK Activity during the Differentiation Process from HMSCs to Osteoblasts  [PDF]
Xiaoling Liao, Shaoying Lu, Yue Zhuo, Christina Winter, Wenfeng Xu, Yingxiao Wang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042709
Abstract: Non-receptor protein kinases FAK and Src play crucial roles in regulating cellular adhesions, growth, migration and differentiation. However, it remains unclear how the activity of FAK and Src is regulated during the differentiation process from mesenchymal stem cells (MSCs) to bone cells. In this study, we used genetically encoded FAK and Src biosensors based on fluorescence resonance energy transfer (FRET) to monitor the FAK and Src activity in live cells during the differentiation process. The results revealed that the FAK activity increased after the induction of differentiation, which peaked around 20–27 days after induction. Meanwhile, the Src activity decreased continuously for 27 days after induction. Therefore, the results showed significant and differential changes of FAK and Src activity upon induction. This opposite trend between FAK and Src activation suggests novel and un-coupled Src/FAK functions during the osteoblastic differentiation process. These results should provide important information for the biochemical signals during the differentiation process of stem cells toward bone cells, which will advance our understanding of bone repair and tissue engineering.
The dual kinase complex FAK-Src as a promising therapeutic target in cancer
Victoria Bolós,Joan Manuel Gasent,Sara López-Tarruella,et al
OncoTargets and Therapy , 2010,
Abstract: Victoria Bolós1,*, Joan Manuel Gasent2,*, Sara López-Tarruella3, Enrique Grande1,#1Pfizer Oncology, Madrid, Spain; 2Hospital Gral. Universitario Marina Alta, Oncology Department, Denia Alicante, 3,#Hospital Clínico San Carlos, Oncology Department, These authors contributed equally to this work, #Center affiliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021). Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and InnovationAbstract: Focal adhesion kinase (FAK) and steroid receptor coactivator (Src) are intracellular (nonreceptor) tyrosine kinases that physically and functionally interact to promote a variety of cellular responses. Plenty of reports have already suggested an additional central role for this complex in cancer through its ability to promote proliferation and anoikis resistance in tumor cells. An important role for the FAK/Src complex in tumor angiogenesis has also been established. Furthermore, FAK and Src have been associated with solid tumor metastasis through their ability to promote the epithelial mesenchymal transition. In fact, a strong correlation between increased FAK/Src expression/phosphorylation and the invasive phenotype in human tumors has been found. Additionally, an association for FAK/Src with resistances to the current anticancer therapies has already been established. Currently, novel anticancer agents that target FAK or Src are under development in a broad variety of solid tumors. In this article we will review the normal cellular functions of the FAK/Src complex as an effector of integrin and/or tyrosine kinase receptor signaling. We will also collect data about their role in cancer and we will summarize the most recent data from the FAK and Src inhibitors under clinical and preclinical development. Furthermore, the association of both these proteins with chemotherapy and hormonal therapy resistances, as a rationale for new combined therapeutic approaches with these novel agents, to abrogate treatment associated resistances, will also be reviewed.Keywords: SRC, FAK, cancer, therapeutic target, FAK inhibitors, SRC inhibitors
Paxillin-Y118 phosphorylation contributes to the control of Src-induced anchorage-independent growth by FAK and adhesion
Sanjay Sachdev, Yahao Bu, Irwin H Gelman
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-12
Abstract: To understand how FAK affects oncogenesis through the phosphorylation of cellular substrates of Src, we analyzed the phosphorylation profile of a panel of Src substrates in parental and v-Src-expressing FAK+/+ and FAK-/- mouse embryo fibroblasts, under conditions of anchorage-dependent (adherent) and -independent (suspension) growth.Total Src-induced cellular tyrosine phosphorylation as well as the number of phosphotyrosyl substrates was higher in suspension versus adherent cultures. Although the total level of Src-induced cellular phosphorylation was similar in FAK+/+ and FAK-/- backgrounds, the phosphorylation of some substrates was influenced by FAK depending on adherence state. Specifically, in the absence of FAK, Src induced higher phosphorylation of p190RhoGAP, paxillin (poY118) and Crk irrespective of adhesion state, PKC-δ (poY311), connexin-43 (poY265) and Sam68 only under adherent conditions, and p56Dok-2 (poY351) and p120catenin (poY228) only under suspension conditions. In contrast, FAK enhanced the Src-induced phosphorylation of vinculin (poY100 and poY1065) and p130CAS (poY410) irrespective of adherence state, p56Dok-2 (poY351) and p120catenin (poY228) only under adherent conditions, and connexin-43 (poY265), cortactin (poY421) and paxillin (poY31) only under suspension conditions. The Src-induced phosphorylation of Eps8, PLC-γ1 and Shc (poY239/poY240) were not affected by either FAK or adherence status. The enhanced anchorage-independent growth of FAK-/-[v-Src] cells was selectively decreased by expression of paxillinY118F, but not by WT-paxillin, p120cateninY228F or ShcY239/240F, identifying for the first time a role for paxillinpoY118 in Src-induced anchorage-independent growth. Knockdown of FAK by siRNA in the human colon cancer lines HT-25 and RKO, resulted in increased paxillinpoY118 levels under suspension conditions as well as increased anchorage-independent growth, supporting the notion that FAK attenuates anchorage-independent growth by suppre
Tyrosine phosphorylation of cortactin by the FAK-Src complex at focal adhesions regulates cell motility
Wenqi Wang, Yang Liu, Kan Liao
BMC Cell Biology , 2011, DOI: 10.1186/1471-2121-12-49
Abstract: Signaling by the FAK-Src complex plays a crucial role in regulating the formation of protein complexes at focal adhesions to which the actin filaments are attached. Cortactin, an F-actin associated protein and a substrate of Src kinase, was found to interact with FAK through its SH3 domain and the C-terminal proline-rich regions of FAK. We found that the autophosphorylation of Tyr397 in FAK, which is necessary for FAK activation, was not required for the interaction with cortactin, but was essential for the tyrosine phosphorylation of the associated cortactin. At focal adhesions, cortactin was phosphorylated at tyrosine residues known to be phosphorylated by Src. The tyrosine phosphorylation of cortactin and its ability to associate with the actin cytoskeleton were required in tandem for the regulation of cell motility. Cell motility could be inhibited by truncating the N-terminal F-actin binding domains of cortactin or by blocking tyrosine phosphorylation (Y421/466/475/482F mutation). In addition, the mutant cortactin phosphorylation mimic (Y421/466/475/482E) had a reduced ability to interact with FAK and promoted cell motility. The promotion of cell motility by the cortactin phosphorylation mimic could also be inhibited by truncating its N-terminal F-actin binding domains.Our results suggest that cortactin acts as a bridging molecule between actin filaments and focal adhesions. The cortactin N-terminus associates with F-actin, while its C-terminus interacts with focal adhesions. The tyrosine phosphorylation of cortactin by the FAK-Src complex modulates its interaction with FAK and increases its turnover at focal adhesions to promote cell motility.Src is a non-receptor cytoplasmic tyrosine kinase activated by integrins and receptor tyrosine kinases [1]. In normal cells, Src is involved in a vast range of physiological functions, including cell proliferation, cytoskeletal regulation, cell shape control, cell-matrix adhesion dynamics and motility [2,3]. In many types
The dual kinase complex FAK-Src as a promising therapeutic target in cancer
Victoria Bolós, Joan Manuel Gasent, Sara López-Tarruella, et al
OncoTargets and Therapy , 2010, DOI: http://dx.doi.org/10.2147/OTT.S6909
Abstract: ual kinase complex FAK-Src as a promising therapeutic target in cancer Review (5527) Total Article Views Authors: Victoria Bolós, Joan Manuel Gasent, Sara López-Tarruella, et al Published Date June 2010 Volume 2010:3 Pages 83 - 97 DOI: http://dx.doi.org/10.2147/OTT.S6909 Victoria Bolós1,*, Joan Manuel Gasent2,*, Sara López-Tarruella3, Enrique Grande1,# 1Pfizer Oncology, Madrid, Spain; 2Hospital Gral. Universitario Marina Alta, Oncology Department, Denia Alicante, 3,#Hospital Clínico San Carlos, Oncology Department, These authors contributed equally to this work, #Center affiliated to the Red Temática de Investigación Cooperativa (RD06/0020/0021). Instituto de Salud Carlos III (ISCIII), Spanish Ministry of Science and Innovation Abstract: Focal adhesion kinase (FAK) and steroid receptor coactivator (Src) are intracellular (nonreceptor) tyrosine kinases that physically and functionally interact to promote a variety of cellular responses. Plenty of reports have already suggested an additional central role for this complex in cancer through its ability to promote proliferation and anoikis resistance in tumor cells. An important role for the FAK/Src complex in tumor angiogenesis has also been established. Furthermore, FAK and Src have been associated with solid tumor metastasis through their ability to promote the epithelial mesenchymal transition. In fact, a strong correlation between increased FAK/Src expression/phosphorylation and the invasive phenotype in human tumors has been found. Additionally, an association for FAK/Src with resistances to the current anticancer therapies has already been established. Currently, novel anticancer agents that target FAK or Src are under development in a broad variety of solid tumors. In this article we will review the normal cellular functions of the FAK/Src complex as an effector of integrin and/or tyrosine kinase receptor signaling. We will also collect data about their role in cancer and we will summarize the most recent data from the FAK and Src inhibitors under clinical and preclinical development. Furthermore, the association of both these proteins with chemotherapy and hormonal therapy resistances, as a rationale for new combined therapeutic approaches with these novel agents, to abrogate treatment associated resistances, will also be reviewed.
The Overexpression of Scaffolding Protein NEDD9 Promotes Migration and Invasion in Cervical Cancer via Tyrosine Phosphorylated FAK and SRC  [PDF]
Ni Sima, Xiaodong Cheng, Feng Ye, Ding Ma, Xing Xie, Weiguo Lü
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074594
Abstract: NEDD9, a focal adhesion scaffolding protein, has been recently proposed to regulate invasion and metastasis in some cancer types, but unknown in cervical cancer. The aim of this study was to determine if NEDD9 was involved in the progression and metastasis of cervical cancer. The experimental results showed NEDD9 protein was overexpressed in cervical cancer compared with normal cervical epithelium tissues. Overexpression of NEDD9 was correlated with histological grading, lymph node metastasis, and FIGO stage of cervical cancer. Silencing NEDD9 resulted in tyrosine dephosphorylation of FAK and SRC oncoproteins, and decreased cell migration and invasion in the cervical carcinoma SiHa and HeLa cells. Overexpression of NEDD9 led to tyrosine phosphorylation of FAK and SRC oncoproteins, and increased cell migration and invasion. Moreover, tyrosine phosphorylation of NEDD9 was significantly decreased via suppressing tyrosine phosphorylation of FAK or SRC, suggesting a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC. In addition, our data showed that silencing NEDD9 decreased Vimentin expression and increased E-cadherin expression in cervical cancer cells, and vice versa. E-cadherin was subject to regulation of NEDD9, FAK and SRC, but altered neither tyrosine-phosphorylated nor total NEDD9. Our findings suggest that NEDD9 is overexpressed in cervical cancer tissues and cells, and overexpressed NEDD9 promotes migration and invasion in cervical carcinoma cells, probably via a positive feedback loop of tyrosine phosphorylation between NEDD9 and FAK or SRC.
FAK、FAKpY397和Src在肝细胞癌中的表达和意义  [PDF]
谷艳娇,张敬坤,包翠芬,苏荣健
重庆医科大学学报 , 2013,
Abstract: 目的:探讨黏着斑激酶(focaladhesionkinase,FAK)、磷酸化黏着斑激酶(phospho-FAKY397,FAKpY397)和类固醇激素受体共活化因子(sceroidrecptorcoactivator,Src)在不同分化程度肝细胞癌(hepatocellularcarcinoma,HCC)中的表达情况以及三者的相关性。方法:通过免疫组织化学法和人工计数法检测44例HCC组织及8例癌旁正常肝脏组织中FAK、FAKpY397和Src的表达。结果:FAK、FAKpY397和Src在HCC组织中表达均高于正常肝脏组织(P=0.027、P=0.041、P=0.030)且三者均与HCC分化程度有关(P=0.026、P=0.045、P=0.005),FAK和Src低分化组阳性率高于高分化组(P=0.015、P=0.002)。HCC组织中三者表达两两之间呈正相关(P=0.000、P=0.000、P=0.000)。结论:HCC组织中FAK、FAKpY397和Src表达与HCC分化程度有关;FAK和Src低分化组阳性率高于高分化组且三者相互之间存在一定相关性。
Epithelial Membrane Protein-2 Promotes Endometrial Tumor Formation through Activation of FAK and Src  [PDF]
Maoyong Fu, Rajiv Rao, Deepthi Sudhakar, Claire P. Hogue, Zach Rutta, Shawn Morales, Lynn K. Gordon, Jonathan Braun, Lee Goodglick, Madhuri Wadehra
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0019945
Abstract: Endometrial cancer is the most common gynecologic malignancy diagnosed among women in developed countries. One recent biomarker strongly associated with disease progression and survival is epithelial membrane protein-2 (EMP2), a tetraspan protein known to associate with and modify surface expression of certain integrin isoforms. In this study, we show using a xenograft model system that EMP2 expression is necessary for efficient endometrial tumor formation, and we have started to characterize the mechanism by which EMP2 contributes to this malignant phenotype. In endometrial cancer cells, the focal adhesion kinase (FAK)/Src pathway appears to regulate migration as measured through wound healing assays. Manipulation of EMP2 levels in endometrial cancer cells regulates the phosphorylation of FAK and Src, and promotes their distribution into lipid raft domains. Notably, cells with low levels of EMP2 fail to migrate and poorly form tumors in vivo. These findings reveal the pivotal role of EMP2 in endometrial cancer carcinogenesis, and suggest that the association of elevated EMP2 levels with endometrial cancer prognosis may be causally linked to its effect on integrin-mediated signaling.
Stretch-Induced Stress Fiber Remodeling and the Activations of JNK and ERK Depend on Mechanical Strain Rate, but Not FAK  [PDF]
Hui-Ju Hsu,Chin-Fu Lee,Andrea Locke,Susan Q. Vanderzyl,Roland Kaunas
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012470
Abstract: Cells within tissues are subjected to mechanical forces caused by extracellular matrix deformation. Cells sense and dynamically respond to stretching of the matrix by reorienting their actin stress fibers and by activating intracellular signaling proteins, including focal adhesion kinase (FAK) and the mitogen-activated proteins kinases (MAPKs). Theoretical analyses predict that stress fibers can relax perturbations in tension depending on the rate of matrix strain. Thus, we hypothesized stress fiber organization and MAPK activities are altered to an extent dependent on stretch frequency.
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