The general goal of this work is to understand the molecular basis of carcinoma invasion. Hemidesmosomes are the molecular basis for stable attachment in most epithelial cells, because these multiprotein structures provide a firm link between the basal lamina and the cytokeratin network. Most carcinoma cells loose their hemidesmosomes. Hemidesmosomes need to be disrupted for a cell to migrate. The focus of our study is to understand how the disassembly of the hemidesmosome is regulated and what its dynamics are. We hypothesize that phosphorylation of key hemidesmosomal components is the molecular basis for regulating hemidesmosome disassembly. We will focus mostly on one of the hemidesmosome components, the integrin alpha6beta4, because this integrin is the key organizer of hemidesmosomes and it has been previously shown that it can be mobilized from hemidesmosomes using a PKC-dependent mechanism that includes serine phosphorylation of the beta4 subunit. Recent data suggest that integrin endocytosis is important for cell migration. We hypothesize PKC alpha regulates the disassembly of the hemidesmosome by regulating both the dissociation and internalization of the alpha6beta4 integrin, allowing the alpha6beta4 integrin to be transported intracellularly towards actin rich protrusions, where it functions in migration.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01CA088919-05
Application #
6841190
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lohrey, Nancy
Project Start
2001-02-08
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2007-01-31
Support Year
5
Fiscal Year
2005
Total Cost
$151,929
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Germain, Emily C; Santos, Tanya M; Rabinovitz, Isaac (2009) Phosphorylation of a novel site on the {beta}4 integrin at the trailing edge of migrating cells promotes hemidesmosome disassembly. Mol Biol Cell 20:56-67
Yoeli-Lerner, Merav; Yiu, Gary K; Rabinovitz, Isaac et al. (2005) Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 20:539-50
Rabinovitz, Isaac; Tsomo, Lobsang; Mercurio, Arthur M (2004) Protein kinase C-alpha phosphorylation of specific serines in the connecting segment of the beta 4 integrin regulates the dynamics of type II hemidesmosomes. Mol Cell Biol 24:4351-60
Mercurio, A M; Bachelder, R E; Rabinovitz, I et al. (2001) The metastatic odyssey: the integrin connection. Surg Oncol Clin N Am 10:313-28, viii-ix
Mercurio, A M; Rabinovitz, I; Shaw, L M (2001) The alpha 6 beta 4 integrin and epithelial cell migration. Curr Opin Cell Biol 13:541-5
Mercurio, A M; Bachelder, R E; Chung, J et al. (2001) Integrin laminin receptors and breast carcinoma progression. J Mammary Gland Biol Neoplasia 6:299-309
Mercurio, A M; Rabinovitz, I (2001) Towards a mechanistic understanding of tumor invasion--lessons from the alpha6beta 4 integrin. Semin Cancer Biol 11:129-41
Rabinovitz, I; Gipson, I K; Mercurio, A M (2001) Traction forces mediated by alpha6beta4 integrin: implications for basement membrane organization and tumor invasion. Mol Biol Cell 12:4030-43