Abstract
Posttranslational modifications of mammalian c-Src N-terminal and C-terminal domains regulate distinct functions. Myristoylation of G2 controls its cell membrane association and phosphorylation of Y419/Y527 controls its activation or inactivation, respectively. We provide evidence that Src-cell membrane association-dissociation and catalytic activation-inactivation are both regulated by acetylation. In EGF-treated cells, CREB binding protein (CBP) acetylates an N-terminal lysine cluster (K5, K7, and K9) of c-Src to promote dissociation from the cell membrane. CBP also acetylates the C-terminal K401, K423, and K427 of c-Src to activate intrinsic kinase activity for STAT3 recruitment and activation. N-terminal domain phosphorylation (Y14, Y45, and Y68) of STAT3 by c-Src activates transcriptionally active dimers of STAT3. Moreover, acetyl-Src translocates into nuclei, where it forms the Src-STAT3 enhanceosome for gene regulation and cancer cell proliferation. Thus, c-Src acetylation in the N-terminal and C-terminal domains play distinct roles in Src activity and regulation.Significance: CBP-mediated acetylation of lysine clusters in both the N-terminal and C-terminal regions of c-Src provides additional levels of control over STAT3 transcriptional activity. Cancer Res; 78(11); 2825-38. ©2018 AACR.
Highlights
Src family kinases are cell membrane–associated nonreceptor protein tyrosine kinases that coordinate various cellular events including differentiation, adhesion, and migration
Among all those putative posttranslational modifications [16, 17], we noticed that human c-Src acetylation was induced by EGF in a time-dependent manner in MCF-7 cells, which was further enhanced by pretreatment of the cells with histone deacetylase (HDAC) inhibitor trichostatin A (TSA) or Sirt deacetylase inhibitor nicotinamide (NAM; Fig. 1A). c-Src Tyr 419 phosphorylation was increased upon EGF and deacetylase inhibitor treatment (Fig. 1A)
We and others have shown that cAMP-response element-binding protein (CREB) binding protein (CBP) can shuttle between cytoplasm and nuclear in quiescent cells or in stimulated cells to interact with cytoplasmic proteins or membrane receptors [19, 20]
Summary
Src family kinases are cell membrane–associated nonreceptor protein tyrosine kinases that coordinate various cellular events including differentiation, adhesion, and migration. Aberrant Src kinase activity has been widely implicated in cancer development, progression, and metastasis [1, 2]. Src has N-terminal and C-terminal regions of similar size. The human c-Src Nterminal region is comprised of a unique domain (UD), an SH3 domain, and an SH2 domain while the C-terminal region contains a catalytic domain (CD) followed by a regulatory tail [2]. Src associates with the cytoplasmic membrane, which depends on. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Chen are the co-first authors of this article
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