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A Protein Kinase C‐Activated Motility Signaling Pathway in Human Breast Cells
Author(s) -
Rotenberg Susan,
Zhao Xin,
De Shatarupa
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.893.17
Subject(s) - marcks , rac1 , microbiology and biotechnology , motility , protein kinase c , cdc42 , phosphorylation , guanine nucleotide exchange factor , signal transduction , gtpase , rac gtp binding proteins , kinase , protein kinase a , pak1 , chemistry , biology
This laboratory has identified and characterized substrates of protein kinase C (PKC) that upon phosphorylation give rise to cell motility, an aspect of metastasis. Each phospho‐protein promotes the formation of activated (GTP‐bound) Rac1, a small GTPase that is known to be instrumental in driving cell movement. By use of the traceable kinase method, we discovered that α‐tubulin and Cdc42 effector protein‐4 (CEP4) are PKC substrates. Phosphorylation of α‐tubulin stimulates its incorporation into microtubules, consequently increasing their stability and prolonged growth and leading to the activation of Rac1. CEP4 undergoes phosphorylation by PKC that results in its release from Cdc42, whereupon CEP4 binds a guanine nucleotide exchange factor (TEM4) that in turn activates Rac1 and results in translocation of IQGAP to the leading edge of the moving cell. Similarly, MARCKS, a well‐known PKC substrate, promotes cell motility. We determined that pseudo‐phosphorylated MARCKS co‐immunoprecipitates with DOCK2, a GEF that is also known to activate Rac1. When each PKC substrate is expressed in its pseudo‐phosphorylated mutant form, the resulting cell motility can be inhibited by Rac inhibitor NSC23766. A model is presented that depicts Rac1 as a node for phosphorylated PKC substrates that consequently promotes the motility phenotype. This work is supported by NIH CA125632.