Core cysteine residues in the Plasminogen-Apple-Nematode (PAN) domain are critical for HGF/c-MET signaling

Pal, Debjani; De, Kuntal; Shanks, Carly M.; Feng, Kai; Yates, Timothy B.; Morrell-Falvey, Jennifer; Davidson, Russell B.; Parks, Jerry M.; Muchero, Wellington

doi:10.1038/s42003-022-03582-8

Title: Core cysteine residues in the Plasminogen-Apple-Nematode (PAN) domain are critical for HGF/c-MET signaling

Journal Article · 01 July 2022 · Communications Biology

DOI: https://doi.org/10.1038/s42003-022-03582-8 · OSTI ID:1875331

^[1]; De, Kuntal ^[1];

^[1]; Feng, Kai ^[1]; Yates, Timothy B. ^[2];

^[1];

^[2]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)

The Plasminogen-Apple-Nematode (PAN) domain, with a core of four to six cysteine residues, is found in > 28,000 proteins across 959 genera. Still, its role in protein function is not fully understood. The PAN domain was initially characterized in numerous proteins, including HGF. Dysregulation of HGF-mediated signaling results in multiple deadly cancers. The binding of HGF to its cell surface receptor, c-MET, triggers all biological impacts. Here, we show that mutating four core cysteine residues in the HGF PAN domain reduces c-MET interaction, subsequent c-MET autophosphorylation, and phosphorylation of its downstream targets, perinuclear localization, cellular internalization of HGF, and its receptor, c-MET, and c-MET ubiquitination. Furthermore, transcriptional activation of HGF/c-MET signaling-related genes involved in cancer progression, invasion, metastasis, and cell survival were impaired. Thus, targeting the PAN domain of HGF may represent a mechanism for selectively regulating the binding and activation of the c-MET pathway.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER); USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1875331

Journal Information:: Communications Biology, Vol. 5, Issue 1; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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