This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Metastasic tumor growth is the principal event leading to death in patients with cancer, however, its molecular basis is presently poorly understood. Metastasic tumor cells generally migrate at a faster rate than normal cells or non-metastasic tumor cells. This observation leads to the hypothesis that increased cell motility (migration) is necessary for cells to become metastasic. Recently, a novel cytosolic-dependent role for the cyclin:CDK inhibitor p27KIP1 in cell motility was identified. It was shown that HGF signaling via the Met receptor resulted in the nuclear export of p27 KIP1 into the cytoplasm. This cytosolic localization was required for p27 KIP1 to induce cell motility and resulted in actin cytoskeletal rearrangements. These results suggest that deregulated signaling in tumor cells induce cytoplasmic import of p27. Our central hypothesis is that in the cytoplasm, p27 assembles into a complex involved in cytoskeletal remodeling and cell migration resulting in increased metastasis. The cytoplasmic relocalization and involvement of p27 in actin cytoskeletal rearrangement are evolutionarily reminiscent of alpha factor pheromone signaling in yeast. Far1p, the yeast cyclin:cdk inhibitor, mediates both a G1 cell cycle arrest in the nucleus and induction of shmoo formation in the cytoplasm that orients the actin cytoskeleton toward the opposite mating partner . In response to alpha factor, Far1p translocates from the nucleus to the cytoplasm and interacts with Cdc24p, a guanine nucleotide exchange factor for Cdc42p. Consistent with this functional analogy, mutation of a Far1p-like sequence motif present in the p27 scatter domain inactivates both cell migration and actin rearrangement, but preserves the cell cycle arrest functions of p27. Our objective is to identify the proteins complexes binding to p27 in the cytoplasm by TAP-tag purification and mass spectrometry analysis.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
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University of Washington
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