Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Jul 15:157:52-61.
doi: 10.1016/j.lfs.2016.05.036. Epub 2016 May 28.

Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis

Ami Patel  1 , Harika Sabbineni  2 , Andrea Clarke  1 , Payaningal R Somanath  3
Affiliations
Review

Novel roles of Src in cancer cell epithelial-to-mesenchymal transition, vascular permeability, microinvasion and metastasis

Ami Patel et al. Life Sci. .

Abstract

The Src-family kinases (SFKs), an intracellularly located group of non-receptor tyrosine kinases are involved in oncogenesis. The importance of SFKs has been implicated in the promotion of tumor cell motility, proliferation, inhibition of apoptosis, invasion and metastasis. Recent evidences indicate that specific effects of SFKs on epithelial-to-mesenchymal transition (EMT) as well as on endothelial and stromal cells in the tumor microenvironment can have profound effects on tumor microinvasion and metastasis. Although, having been studied extensively, these novel features of SFKs may contribute to greater understanding of benefits from Src inhibition in various types of cancers. Here we review the novel role of SFKs, particularly c-Src in mediating EMT, modulation of tumor endothelial-barrier, transendothelial migration (microinvasion) and metastasis of cancer cells, and discuss the utility of Src inhibitors in vascular normalization and cancer therapy.

Keywords: EMT; Metastasis; Microinvasion; Src; Vascular permeability.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Activity modulation of SFKs
In inactive conformation, SFKs bind to the cell membrane via lipids in the N-terminus. Phosphorylation of Tyr527 on c-terminal regulatory tail keeps them inactive by binding to the SH2 domain. Upon ligand binding to RTKs, SH2 domain of SFK is recruited to the phosphorylated docking sites on the cytosolic domain of RTKs exposing the Tyr527 for dephosphorylation by protein tyrosine phosphatases such as PTPα, Shp2 etc. This allows the activation of Tyr416 in the activation loop leading to the complete activation of SFKs to perform cellular functions. KD-kinase domain; RTK-receptor tyrosine kinase; PTyr527-phosphorylated tyrosine 527; PTPα- protein tyrosine phosphatase alpha; KD-kinase domain.
Figure 2
Figure 2. Role of SFKs in promoting epithelial-to-mesenchymal transition (EMT) in prostate cancer
Enhanced expression of Src (and other SFKs) in prostate cancer is associated with disassembly of AJs and TJs due to decrease in E-cadherin and Integrin α6β4 (Iα6β4) as well as increase in N-cadherin and Integrin α5β1 (Iα5β1) associated with increase in the expression of mesenchymal markers such as vimentin and decrease in epithelial markers such as cytokeratins. Phosphorylation of paxillin at Y118 by FAK enhances cell motility and survival facilitating the cells to acquire mesenchymal properties and ability to invade local tissues. [SFK, Src family of kinases; FAK, focal adhesion kinase; AJ, adherens junction; TJ, tight junction]
Figure 3
Figure 3. Modulation of tumor vascular permeability and microinvasion by SFKs
VEGF-A binding to VEGFR2 activates intrinsic tyrosine kinase activity of the receptors resulting in their transphosphorylation, recruitment of Src and subsequent phosphorylation of VE-cadherin by Src in the junctional complex. This results in the dissociation of junctional complex proteins such as VE-cadherin and β-catenin, thus disrupting endothelial barrier, and releasing β-arrestin from VE-cadherin causing internalization of VE-cadherins into vesicles through endocytosis, thus rendering the barrier permeable to intravasation of inflammatory cells. Phosphorylation of MLCK by Src results in cytoskeletal rearrangements and cellular contractions leading to dissociation of AJs, thus contributing to leaky endothelial barrier. SFK-mediated activation of PI3K/Akt signaling pathway regulates phosphorylation of FoxO1 and its cytosolic accumulation thereby preventing claudin-5 expression and permeability control in addition to promoting growth, survival and transcriptional regulation of tumor cells through phosphorylation of BAD, mTOR, S6K and GSK3. (VEGF, Vascular endothelial growth factor; MLCK, Myosin light chain kinase; AJ, Adherens junction; BAD, Bcl-2 associated death promoter; mTOR, Mammalian target of rapamycin; S6K, Ribosomal S6 kinase; GSK-3, Glycogen synthase kinase-3)
Figure 4
Figure 4. Role of SFKs in recruiting inflammatory and bone marrow derived cells
Integrin αvβ3 a receptor for extracellular matrix proteins on bone metastatic tumor cells bind to osteopontin expressed by bone stromal cells causing activation of FAK, which recruits other signaling molecules including c-Src. C-Src enhances proliferation and survival through JNK pathway by phosphorylating CAS in addition to the recruitment of BMDCs by phosphorylating integrin β3. [FAK, focal adhesion kinase; CAS, Crk-associated substrate; BMDC, bone marrow derived cells]
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Li S. Src-family kinases in the development and therapy of Philadelphia chromosome- positive chronic myeloid leukemia and acute lymphoblastic leukemia. Leuk Lymphoma. 2008;49(1):19–26. - PMC - PubMed
    1. Zhang S, Yu D. Targeting Src family kinases in anti-cancer therapies: turning promise into triumph. Trends Pharmacol Sci. 2012;33(3):122–8. - PMC - PubMed
    1. Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000;19(49):5636–42. - PubMed
    1. Somanath PR, Malinin NL, Byzova TV. Cooperation between integrin alphavbeta3 and VEGFR2 in angiogenesis. Angiogenesis. 2009;12(2):177–85. - PMC - PubMed
    1. Schlessinger J. New roles for Src kinases in control of cell survival and angiogenesis. Cell. 2000;100(3):293–6. - PubMed

MeSH terms

Substances