A hotspot phosphorylation site on SHP2 drives oncoprotein activation and drug resistance
Open accessPublished version of a preprint
Abstract
SHP2 is a phosphatase and a critical mediator of receptor tyrosine kinase (RTK)-driven RAS/mitogen-activated protein kinase (MAPK) signaling. Despite promising preclinical data, SHP2 inhibitors have shown minimal clinical efficacy, with no defined clinical mechanisms of primary resistance. Here, we elucidate phosphorylation of SHP2 at tyrosine 62 (pY62) as a hotspot phosphorylation site in the proteome and RTK-driven tumor types in patients. We demonstrate that SRC family kinases directly phosphorylate SHP2 at Y62, downstream of but not directly phosphorylated by RTKs. Using biochemical and biophysical analyses, we show that SHP2 Y62D enforces an open, active conformation, resulting in constitutive phosphatase activation that is sufficient to activate MAPK signaling and confer resistance to allosteric SHP2 inhibitors. These findings establish that SHP2 pY62 is a phosphorylation hotspot phenocopying mutational activation, a mechanism of primary resistance to SHP2 inhibitors, and a cancer drug target distinct from wildtype SHP2.
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- Authors
- Karunaraj, P., Scheele, R., Wells, M. L., Rathod, R., Gokulu, I. S., Abrahamson, S. R., Taylor, L., Chowdhury, L., Kazmi, A., Song, W., Hornbeck, P. V., Li, J., Glasgow, A., & Vasan, N.
- Affiliations
- Columbia University Irving Medical Center (US)
- Memorial Sloan Kettering Cancer Center (US)
- SUNY Downstate Health Sciences University (US)
- WuXi AppTec (China) (CN)
- Cell Signaling Technology (United States) (US)
- Corresponding author
- Vasan, Neil
- ORCID
- Venue
- Nature Communications
- Published
- 2026-03-03
- Volume
- 17
- Issue
- 1
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12262427
- OpenAlex
- W7133357120
- Cited by
- 7
- References
- 9
- Citations by year
- 2026: 5 · 2025: 2
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (cc-by)
- Funders
- the Louis V. Gerstner Jr. Scholars Program at Columbia University Irving Medical Center
- U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R00GM135529)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- SHP2, Src family kinases, RAS/MAPK pathway, receptor tyrosine kinase signaling, SHP2 inhibitors, drug resistance, protein conformation, cancer drug targets
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