LNK suppresses interferon signaling in melanoma.

LNK (SH2B3) is a key negative regulator of JAK-STAT signaling which has been extensively studied in malignant hematopoietic diseases. We found that LNK is significantly elevated in cutaneous melanoma; this elevation is correlated with hyperactive signaling of the RAS-RAF-MEK pathway. Elevated LNK enhances cell growth and survival in adverse conditions. Forced expression of LNK inhibits signaling by interferon-STAT1 and suppresses interferon (IFN) induced cell cycle arrest and cell apoptosis. In contrast, silencing LNK expression by either shRNA or CRISPR-Cas9 potentiates the killing effect of IFN. The IFN-LNK signaling is tightly regulated by a negative feedback mechanism; melanoma cells exposed to IFN upregulate expression of LNK to prevent overactivation of this signaling pathway. Our study reveals an unappreciated function of LNK in melanoma and highlights the critical role of the IFN-STAT1-LNK signaling axis in this potentially devastating disease. LNK may be further explored as a potential therapeutic target for melanoma immunotherapy.

Citation

Ling-Wen Ding, Qiao-Yang Sun, Jarem J Edwards, Lucia Torres Fernández, Xue-Bin Ran, Si-Qin Zhou, Richard A Scolyer, James S Wilmott, John F Thompson, Ngan Doan, Jonathan W Said, Nachiyappan Venkatachalam, Jin-Fen Xiao, Xin-Yi Loh, Maren Pein, Liang Xu, David W Mullins, Henry Yang, De-Chen Lin, H Phillip Koeffler. LNK suppresses interferon signaling in melanoma. Nature communications. 2019 May 20;10(1):2230

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PMID: 31110180

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