Decline in arylsulfatase B (N-acetylgalactosamine-4-sulfatase) leads to increased EGFR expression due to SHP2 inhibition and JNK activation in prostate

Bhattacharyya, S.
Feferman, L.
Han, X.
Ouya, Y.
Zhang, F.
Linhardt, Robert J.
Tobacman, J.K.
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Biology , Chemistry and chemical biology , Chemical and biological engineering , Biomedical engineering
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Decline in arylsulfatase B (N-acetylgalactosamine-4-sulfatase) leads to increased EGFR expression due to SHP2 inhibition and JNK activation in prostate, S. Bhattacharyya, L. Feferman, X. Han, Y. Ouya, F. Zhang, R. J. Linhardt, J. K. Tobacman, Journal of Biological Chemistry, 293, 11076–11087, 2018.
Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear. Here, we show that SHP2 binds preferentially C4S, rather than chondroitin 6-sulfate, and confirm that SHP2 activity declines when ARSB is silenced. The reduction in ARSB activity, and the resultant increase in C4S, increased the expression of EGFR (Her1/ErbB1) in human prostate stem and epithelial cells. The increased expression of EGFR occurred after 1) the decline in SHP2 activity, 2) enhanced c-Jun N-terminal kinase (JNK) activity, 3) increased nuclear DNA binding by c-Jun and c-Fos, and 4) EGFR promoter activation. In response to exogenous EGF, there was increased bromodeoxyuridine incorporation, consistent with enhanced cell proliferation. These findings indicated that ARSB and chondroitin 4-sulfation affect the activation of an important dual phosphorylation threonine–tyrosine kinase and the mRNA expression of a critical tyrosine kinase receptor in prostate cells. Restoration of ARSB activity with the associated reduction in C4S may provide a new therapeutic approach for managing malignancies in which EGFR-mediated tyrosine kinase signaling pathways are active.
Journal of Biological Chemistry, 293, 11076–11087
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Rensselaer Polytechnic Institute, Troy, NY
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