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503803 
Journal Article 
The suppressor of metastasis Nm23-H1 interacts with the Cdc42 Rho family member and the pleckstrin homology domain of oncoprotein Dbl-1 to suppress cell migration 
Murakami, M; Meneses, PI; Lan, K; Robertson, ES 
2008 
Yes 
Cancer Biology & Therapy
ISSN: 1538-4047 
7 
5 
677-688 
English 
Tumor invasion and metastasis is regulated by a number of cellular molecules known to be involved in signaling and cytoskeletal rearrangement. One of these molecules is the suppressor of tumor metastasis Nm23-H1 which linked to invasiveness and metastatic potential of human cancers. Nm23-H1 expression is downregulated in human melanoma and invasive breast carcinoma. Recent studies have shown an association between the Nm23-H1 and oncoprotein Dbl-1 which is associated with guanine exchange and belongs to a family of Guanine Exchange Factors (GEF). In this report we show a direct interaction in vitro and in human B cells and specifically identified the pleckstrin homology domain of Dbl-1 as the domain which binds to Nm23-H1. Furthermore, Nm23-H1 and Dbl-1 colocalized in the cytoplasm of CCS-7 cells when expressed exogenously and showed predominant signals at the periphery of the cells particularly at the plasma membrane. Interestingly, Dbl-1 and Cdc42 expression rescued the suppressive activities of Nm23-H1 in cell migration assays. We show that Cdc42 a regulatory protein involved in cytoskeletal reorganization, cell growth and development can bind to Nm23-H1 and the kinase deficient mutant H118F but only weakly to the mutant P96S which lacks the ability to suppress cell migration and metastasis. Cdc42 also colocalized with Nm23-H1 and the Dbl-1 proteins as specific punctate signals in the cytoplasm and at the cell membrane. Nm23-H1 also lead to the reduction in membrane ruffles and protuberances when expressed with Dbl-1 and Cdc42. Suprisingly, Nm23-H1 interacted with Cdc42 as well as Rac1 but somewhat weaker with RhoA. These studies suggests that Nm23-H1 can negatively regulate cell migration and tumor metastasis by modulating the activity of Cdc42 and possibly other Rho family members through interaction with Dbl-1. 
Nm23-H1; Dbl-1; cell migration; Cdc42; Rac1; nucleoside diphosphate kinase; actin cytoskeleton; tumor-metastasis; proto-oncogene; n-myc; gtpases; activation; proteins; association; expression