Abstract
The Ste20-like kinase, SLK, is involved in the control of cell motility through its effects on actin reorganization and focal adhesion turnover. Here we investigated the role of SLK in chemotaxis downstream of the tyrosine kinase receptor, HER2/ErbB2/Neu, which is frequently overexpressed in human breast cancers. Our results show that SLK is required for the efficient cell migration of human and mouse mammary epithelial cell lines in the presence of the Neu activator, heregulin, as a chemoattractant. SLK activity is stimulated by heregulin treatment or by overexpression of activated Neu. Phosphorylation of tyrosine 1201 or tyrosines 1226/7 on Neu is a key event for SLK activation and cell migration, and cancer cell invasion mediated by these tyrosines is inhibited by kinase-inactive SLK. Signaling pathway inhibitors show that Neu-mediated SLK activation is dependent on MEK, PI3K, PLCgamma and Shc signaling. Furthermore, heregulin-stimulated SLK activity requires signals from the focal adhesion proteins, FAK and src. Finally, phospho-FAK analysis shows that SLK is required for Neu-dependent focal adhesion turnover. Together, these studies define an interaction between Neu and SLK signaling in the regulation of cancer cell motility.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Blotting, Western
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / pathology
-
Catalytic Domain / genetics
-
Cell Line
-
Cell Line, Tumor
-
Cell Movement / drug effects
-
Cell Movement / genetics
-
Cell Movement / physiology*
-
Chemotaxis / drug effects
-
Focal Adhesion Kinase 1 / genetics
-
Focal Adhesion Kinase 1 / metabolism
-
HeLa Cells
-
Humans
-
Immunoprecipitation
-
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
-
Mitogen-Activated Protein Kinase Kinases / metabolism
-
Mutation
-
Neuregulin-1 / pharmacology
-
Phosphatidylinositol 3-Kinases / metabolism
-
Phosphoinositide-3 Kinase Inhibitors
-
Phospholipase C gamma / antagonists & inhibitors
-
Phospholipase C gamma / metabolism
-
Phosphorylation
-
Protein Binding
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism*
-
RNA, Small Interfering / genetics
-
Receptor, ErbB-2 / genetics
-
Receptor, ErbB-2 / metabolism*
-
Signal Transduction / drug effects
-
Transfection
-
Tyrosine / metabolism
Substances
-
Neuregulin-1
-
Phosphoinositide-3 Kinase Inhibitors
-
RNA, Small Interfering
-
Tyrosine
-
SLK protein, human
-
ERBB2 protein, human
-
Receptor, ErbB-2
-
Focal Adhesion Kinase 1
-
PTK2 protein, human
-
Protein Serine-Threonine Kinases
-
Mitogen-Activated Protein Kinase Kinases
-
Phospholipase C gamma