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Cited by 22Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsCancer Mechanisms and Therapy

Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain

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Estevam, Gabriella O, Linossi, Edmond M, Macdonald, Christian B, Espinoza, Carla A, Michaud, Jennifer M, Coyote-Maestas, Willow, Collisson, Eric A, Jura, Natalia +1 more·2024·eLife
DOI 10.7554/elife.91619PMC PMC11398868

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Abstract

MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild-type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a β5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.

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  • Until recently, RTK MAVEs focused on mechanisms of receptor activation and resistance to a panel of RTK inhibitors, exemplified by studies of the MET receptor.

    “Nevertheless, MAVEs for RTKs are less well developed than for GPCRs, until recently focusing on mechanisms of receptor activation and resistance to a panel of RTK inhibitors, exemplified by studies of the MET receptor for hepatocyte growth factor (113).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [113]

    The Introduction describes a deep mutational scan of MET to identify activating and inactivating mutations, supporting MET as an example of an RTK MAVE focused on activation. The Results section on cancer-associated and resistance mutations compares the scan with previously reported resistance mutations, but says the screen was conducted in the absence of an inhibitor; it does not report testing resistance to a panel of RTK inhibitors. Our copy also does not establish the comparison with GPCR MAVEs. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • MAVEs for RTKs are less well developed than for GPCRs.

    “Nevertheless, MAVEs for RTKs are less well developed than for GPCRs, until recently focusing on mechanisms of receptor activation and resistance to a panel of RTK inhibitors, exemplified by studies of the MET receptor for hepatocyte growth factor (113).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [113]

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Authors
Estevam, G. O., Linossi, E. M., Macdonald, C. B., Espinoza, C. A., Michaud, J. M., Coyote-Maestas, W., Collisson, E. A., Jura, N., & Fraser, J. S.
Affiliations
  • University of California, San Francisco (US)
  • Tetrad Graduate Program, University of California, San Francisco
  • QB3 (US)
Corresponding author
Fraser, James S
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-09-13
Volume
12
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.91619
PMC
PMC11398868
OpenAlex
W4387253564
Cited by
22
References
6
Citations by year
2026: 5 · 2025: 10 · 2024: 6 · 2023: 1
FWCI
3.89
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Cancer Institute (CA239604)
  • Howard Hughes Medical Institute (Hanna Gray Fellowship)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords
MET receptor tyrosine kinase, kinase domain mutations, juxtamembrane domain, MET exon 14 skipping, deep mutational scanning, hydrophobic interactions, activating mutations, drug resistance mutations, cancer

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