Upregulation of the scaffolding protein HEF1, also known as NEDD9 and Cas-L, has recently been identified as a pro-metastatic stimulus in a number of different solid tumors, and has also been strongly associated with pathogenesis of BCR-Abl-dependent tumors. As the evidence mounts for HEF1/NEDD9/Cas-L as a key player in metastatic cancer, it is timely to review the molecular regulation of HEF1/NEDD9/Cas-L. Most of the mortality associated with cancer arises from uncontrolled metastases, thus a better understanding of the properties of proteins specifically associated with promotion of this process may yield insights that improve cancer diagnosis and treatment. In this review, we summarize the extensive literature regarding HEF1/NEDD9/Cas-L expression and function in signaling relevant to cell attachment, migration, invasion, cell cycle, apoptosis, and oncogenic signal transduction. The complex function of HEF1/NEDD9/Cas-L revealed by this analysis leads us to propose a model in which alleviation of cell cycle checkpoints and acquired resistance to apoptosis is permissive for a HEF1/NEDD9/Cas-L-promoted pro-metastatic phenotype.
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Acknowledgments MKS and EAG were supported by NIH RO1 CA63366, a Department of Defense OCRF IDEA Award, Pennsylvania Tobacco Settlement Funds, and a grant from the Susan B. Komen Foundation (to EAG), and by an Appropriation from the Commonwealth of Pennsylvania, and by NIH core Grant CA-06927 (to Fox Chase Cancer Center). SS was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labor, and Welfare of Japan. GMO’N is the NSW Cancer Council Career Development Fellow. LC is supported by an Australian Post-graduate Award and is a NSW Cancer Institute Scholar.
- Scaffolding adaptor protein
- Signal transduction