Novel p27kip1 C-Terminal Scatter Domain Mediates Rac-Dependent Cell Migration Independent of Cell Cycle Arrest Functions Export

@article{citeulike:4099807, abstract = {Hepatocyte growth factor (HGF) signaling via its receptor, the proto-oncogene Met, alters cell proliferation and motility and has been associated with tumor metastasis. HGF treatment of HepG2 human hepatocellular carcinoma cells induces cell migration concomitant with increased levels of the p27kip1 cyclin-cdk inhibitor. HGF signaling resulted in nuclear export of endogenous p27 to the cytoplasm, via Ser-10 phosphorylation, where it colocalized with F-actin. Introduction of transducible p27 protein (TATp27) was sufficient for actin cytoskeletal rearrangement and migration of HepG2 cells. TATp27 mutational analysis identified a novel p27 C-terminal domain required for cell migration, distinct from the N-terminal cyclin-cyclin-dependent kinase (cdk) binding domain. Loss or disruption of the p27 C-terminal domain abolished both actin rearrangement and cell migration. The cell-scattering activity of p27 occurred independently of its cell cycle arrest functions and required cytoplasmic localization of p27 via Ser-10 phosphorylation. Furthermore, Rac GTPase was necessary for p27-dependent migration but alone was insufficient for HepG2 cell migration. These results predicted a migration defect in p27-deficient cells. Indeed, p27-deficient primary fibroblasts failed to migrate, and reconstitution with TATp27 rescued the motility defect. These observations define a novel role for p27 in cell motility that is independent of its function in cell cycle inhibition. 10.1128/MCB.23.1.216-228.2003}, author = {Mcallister, Sandra S. and Becker-Hapak, Michelle and Pintucci, Giuseppe and Pagano, Michele and Dowdy, Steven F.}, citeulike-article-id = {4099807}, citeulike-linkout-0 = {http://dx.doi.org/10.1128/MCB.23.1.216-228.2003}, citeulike-linkout-1 = {http://mcb.asm.org/cgi/content/abstract/23/1/216?ijkey=2fe7c1dc1cafea859425b8e75d99e0b181772228&keytype2=tf_ipsecsha}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/12482975}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=12482975}, day = {1}, doi = {10.1128/MCB.23.1.216-228.2003}, journal = {Mol. Cell. Biol.}, keywords = {migration, p27, rac}, month = {January}, number = {1}, pages = {216--228}, posted-at = {2009-02-25 18:36:38}, priority = {2}, title = {Novel p27kip1 C-Terminal Scatter Domain Mediates Rac-Dependent Cell Migration Independent of Cell Cycle Arrest Functions}, url = {http://dx.doi.org/10.1128/MCB.23.1.216-228.2003}, volume = {23}, year = {2003} }

TY - JOUR ID - citeulike:4099807 L3 - citeulike-article-id:4099807 N2 - Hepatocyte growth factor (HGF) signaling via its receptor, the proto-oncogene Met, alters cell proliferation and motility and has been associated with tumor metastasis. HGF treatment of HepG2 human hepatocellular carcinoma cells induces cell migration concomitant with increased levels of the p27kip1 cyclin-cdk inhibitor. HGF signaling resulted in nuclear export of endogenous p27 to the cytoplasm, via Ser-10 phosphorylation, where it colocalized with F-actin. Introduction of transducible p27 protein (TATp27) was sufficient for actin cytoskeletal rearrangement and migration of HepG2 cells. TATp27 mutational analysis identified a novel p27 C-terminal domain required for cell migration, distinct from the N-terminal cyclin-cyclin-dependent kinase (cdk) binding domain. Loss or disruption of the p27 C-terminal domain abolished both actin rearrangement and cell migration. The cell-scattering activity of p27 occurred independently of its cell cycle arrest functions and required cytoplasmic localization of p27 via Ser-10 phosphorylation. Furthermore, Rac GTPase was necessary for p27-dependent migration but alone was insufficient for HepG2 cell migration. These results predicted a migration defect in p27-deficient cells. Indeed, p27-deficient primary fibroblasts failed to migrate, and reconstitution with TATp27 rescued the motility defect. These observations define a novel role for p27 in cell motility that is independent of its function in cell cycle inhibition. 10.1128/MCB.23.1.216-228.2003 IS - 1 JF - Mol. Cell. Biol. EP - 228 TI - Novel p27kip1 C-Terminal Scatter Domain Mediates Rac-Dependent Cell Migration Independent of Cell Cycle Arrest Functions VL - 23 SP - 216 KW - migration KW - p27 KW - rac AU - Mcallister, Sandra AU - Becker-Hapak, Michelle AU - Pintucci, Giuseppe AU - Pagano, Michele AU - Dowdy, Steven PY - 2003/01/01/ UR - http://dx.doi.org/10.1128/MCB.23.1.216-228.2003 ER -