Ras-Directed N-Glycoproteins Are Novel Early Biomarkers for Tumorigenesis and Malignant Transformation and Therapeutic Targets of Neurofibromatosis Type 1
Final rept. 1 Sep 2011-31 May 2014
M D ANDERSON CANCER CENTER HOUSTON TX
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Neurofibromatosis type I is the most common familial cancer predisposition syndrome, the hallmark is the formation of neurofibromas, some of which will develop MPNSTs. In this report, glycoproteins are highly expressed in MPNST cell lines, MPNST clinical specimens, colon and pancreatic cancer cell lines with Kras mutations. Inhibition of protein glycosylation significantly inhibits the proliferation, migration and invasion of MPNST cell lines and inhibits the glycosylation and phosphorylation of tyrosine kinase receptors. Active Ras regulates MGAT5B expression and knockdown of MGAT5B significantly inhibits the phosphorylation of general tyrosine kinase receptors and their intracellular signaling. AKT interacts with and phosphorylates Ser192 in MGAT5B in MPNST cells. Moreover, wild type MGAT5B protein locates in the Golgi apparatus whereas mutated MGAT5BS192A protein retains in the ER and cytoplasm to inhibit MPNST lung tumor metastasis. In addition, PI3 kinase inhibition prevents MGAT5B trafficking from the cytoplasm to the Golgi apparatus to attenuate MGAT5B-mediated glycosylation and phosphorylation of kinase receptors. Targeting MGAT5-mediated glycosylation of general kinase receptors may provide a novel therapeutic approach for the treatment of MPNSTs and Ras-related malignancies.
- Medicine and Medical Research