Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

Abstract

Cancer progression requires a significant reprogramming of cellular signaling to support the essential tumor-specific processes that include hyperproliferation, invasion (for solid tumors) and survival of metastatic colonies. NEDD9 (also known as CasL and HEF1) encodes a multi-domain scaffolding protein that assembles signaling complexes regulating multiple cellular processes relevant to cancer. These include responsiveness to signals emanating from the T and B cell receptors, integrins, chemokine receptors, and receptor tyrosine kinases, as well as cytoplasmic oncogenes such as BCR-ABL and FAK- and SRC-family kinases. Downstream, NEDD9 regulation of partners including CRKL, WAVE, PI3K/AKT, ERK, E-cadherin, Aurora-A (AURKA), HDAC6, and others allow NEDD9 to influence functions as pleiotropic as migration, invasion, survival, ciliary resorption, and mitosis. In this review, we summarize a growing body of preclinical and clinical data that indicate that while NEDD9 is itself non-oncogenic, changes in expression of NEDD9 (most commonly elevation of expression) are common features of tumors, and directly impact tumor aggressiveness, metastasis, and response to at least some targeted agents inhibiting NEDD9-interacting proteins. These data strongly support the relevance of further development of NEDD9 as a biomarker for therapeutic resistance. Finally, we briefly discuss emerging evidence supporting involvement of NEDD9 in additional pathological conditions, including stroke and polycystic kidney disease.

Downregulation of NEDD9 by apigenin suppresses migration, invasion, and metastasis of colorectal cancer cells

“…A high level of NEDD9 has been found in the colorectal cancer patients (Shagisultanova et al, 2015). To learn whether NEDD9 is also highly expressed in colorectal cancer cell lines, we have examined NEDD9 protein level in CRL1807 non-transformed human colonocytes and colorectal carcinoma DLD1 and SW480 cells using immunoblotting analysis.…”

Significance of serum neural precursor cell‑expressed developmentally downregulated protein 9 in melanoma

“…Genomic modifications, such as chromosomal gain and loss, account for the development and/or invasiveness of several cancer types. Among these events, chromosome 6p gain has been particularly associated with several malignancies and their prognosis, including lymphoma, retinoblastoma, multiple myeloma and non-small-cell lung cancer (NSCLC), and the Nedd9 gene was found to be constantly upregulated in this amplified region in metastatic, but not in primary, melanoma cells excessively expressing the NEDD9 protein, which promotes metastasis in melanoma (7,12). Furthermore, NEDD9 knockdown resulted in inhibition of proliferation and invasion of melanoma cells; thus, continued NEDD9 expression was found to be necessary for melanoma cells to invade and metastasize (12).…”

“…The Cas proteins have been thoroughly investigated, and even mildly overexpressed levels of these proteins have been found to be correlated with poor survival, resistance to chemotherapy and metastasis in malignancies such as melanoma, lung cancer, glioblastoma, and breast cancer. These proteins have not only been associated with cancer, but they have also been reported to be associated with other non-malignant conditions, including polycystic kidney disease (7).…”

“…Subsequently, focal adhesion kinase (FAK) and the Src and ABL families of kinases are activated and they, in turn, phosphorylate NEDD9 substrate domain even more extensively, which provides multiple binding sites, i.e., Y189, Y317 and Y279, for downstream effectors. FAK phosphorylation of the DYDY motif in the NEDD9 C-terminal generates a binding site for Src kinase, which enables NEDD9 to operate in migration and other signaling functions (7). Furthermore, Y189 phosphorylation by FAK and Src kinases is involved in focal adhesion.…”

“…It also activates matrix metalloproteinases (MMPs) and mediates actin branching and lamellipodia formation. NEDD9 downregulates E-cadherin expression by upregulating certain transcription factors, such as SLUG and SNAIL, modulates the Src-dependent E-cadherin removal from junctions and furthers invasion by degradation of the basal membrane through active MMP2 production (7).…”