Phosphorylation state of Ser(165) in α-tubulin is a toggle switch that controls proliferating human breast tumors Journal Article


Authors: Markovsky, E.; de Stanchina, E.; Itzkowitz, A.; Haimovitz-Friedman, A.; Rotenberg, S. A.
Article Title: Phosphorylation state of Ser(165) in α-tubulin is a toggle switch that controls proliferating human breast tumors
Abstract: Engineered overexpression of protein kinase Cα (PKCα) is known to phosphorylate Ser165 in α-tubulin resulting in stimulated microtubule dynamics and cell motility, and activation of an epithelial-mesenchymal transition (EMT) in non-transformed human breast cells. Here it is shown that endogenous phosphorylation of native α-tubulin in two metastatic breast cell lines, MDA-MB-231-LM2–4175 and MDA-MB-468 is detected at PKC phosphorylation sites. α-Tubulin mutants that simulated phosphorylated (S165D) or non-phosphorylated (S165 N) states were stably expressed in MDA-MB-231-LM2–4175 cells. The S165D-α-tubulin mutant engendered expression of the EMT biomarker N-cadherin, whereas S165 N-α-tubulin suppressed N-cadherin and induced E-cadherin expression, revealing a ‘cadherin switch’. S165 N-α-tubulin engendered more rapid passage through the cell cycle, induced shorter spindle fibers and exhibited more rapid proliferation. In nude mice injected with MDA-MB-231-LM2–4175 cells, cells expressing S165 N-α-tubulin (but not the S165D mutant) produced hyper-proliferative lung tumors with increased tumor incidence and higher Ki67 expression. These results implicate the phosphorylation state of Ser165 in α-tubulin as a PKC-regulated molecular switch that causes breast cells to exhibit either EMT characteristics or hyper-proliferation. Evaluation of genomic databases of human tumors strengthens the clinical significance of these findings. © 2018 Elsevier Inc.
Keywords: cell cycle; biomarker; protein kinase c; emt; cadherin switch; spindle fibers
Journal Title: Cellular Signalling
Volume: 52
ISSN: 0898-6568
Publisher: Elsevier Inc.  
Date Published: 2018-12-01
Start Page: 74
End Page: 82
Language: English
DOI: 10.1016/j.cellsig.2018.08.021
PROVIDER: scopus
PUBMED: 30176291
DOI/URL:
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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