Evidence map›Paper›PMID 30644389›Full record

ArticleNature communications2019

Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation.

Yoshihito Kano, Teklab Gebregiworgis, Christopher B Marshall, Nikolina Radulovich, Betty P K Poon, Jonathan St-Germain, Jonathan D Cook, Ivette Valencia-Sama, Benjamin M M Grant, Silvia Gabriela Herrera and 9 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers.

0numbers the graph read from it
0cells of the map it votes in
67citing papers in PubMed
4.7field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

67 citing papers in PubMed, 97 citations in OpenAlex.

  1. Review
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7 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 6 institutions in 2 countries.

Yoshihito KanoDepartment of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
Teklab GebregiworgisPrincess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.ORCID http://orcid.org/0000-0002-1489-4813
Christopher B MarshallPrincess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Nikolina RadulovichPrincess Margaret Cancer Centre, University Health Network and Department of Pathology, University of Toronto, Toronto, ON, M5G 1L7, Canada.
Betty P K PoonDepartment of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
Jonathan St-GermainPrincess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Jonathan D CookDepartment of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
Ivette Valencia-SamaDepartment of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
Benjamin M M GrantPrincess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Silvia Gabriela HerreraLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
Jinmin MiaoDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, USA.
Brian RaughtPrincess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Meredith S IrwinPeter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, 5G OA4, Canada.
Jeffrey E LeeDepartment of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
Jen Jen YehLineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.
Zhong-Yin ZhangDepartment of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, USA.
Ming-Sound TsaoPrincess Margaret Cancer Centre, University Health Network and Department of Pathology, University of Toronto, Toronto, ON, M5G 1L7, Canada.ORCID http://orcid.org/0000-0002-9160-5405
Mitsuhiko IkuraPrincess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
Michael OhhDepartment of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada. michael.ohh@utoronto.ca.ORCID http://orcid.org/0000-0001-7600-4751
University Health Network · CAUniversity of Toronto · CAPurdue University West Lafayette · USUniversity of North Carolina at Chapel Hill · USHospital for Sick Children · CASt. Michael's Hospital · CA

Funding

Tumor Subtypes and Therapy Response in Pancreatic CancerR01CA199064 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI TSAI, SUSAN, YEH, JEN JEN · 2016 to 2021
$4.4M
Development of SHP2 inhibitors for targeted anti-cancer therapyR01CA207288 · NCI · PURDUE UNIVERSITY · PI ZHANG, ZHONG-YIN · 2017 to 2021
$2.3M
NCI NIH HHS R01 CA199064NCI NIH HHS R01 CA207288
6 · The paper itself

Abstract

Deregulation of the RAS GTPase cycle due to mutations in the three RAS genes is commonly associated with cancer development. Protein tyrosine phosphatase SHP2 promotes RAF-to-MAPK signaling pathway and is an essential factor in RAS-driven oncogenesis. Despite the emergence of SHP2 inhibitors for the treatment of cancers harbouring mutant KRAS, the mechanism underlying SHP2 activation of KRAS signaling remains unclear. Here we report tyrosyl-phosphorylation of endogenous RAS and demonstrate that KRAS phosphorylation via Src on Tyr32 and Tyr64 alters the conformation of switch I and II regions, which stalls multiple steps of the GTPase cycle and impairs binding to effectors. In contrast, SHP2 dephosphorylates KRAS, a process that is required to maintain dynamic canonical KRAS GTPase cycle. Notably, Src- and SHP2-mediated regulation of KRAS activity extends to oncogenic KRAS and the inhibition of SHP2 disrupts the phosphorylation cycle, shifting the equilibrium of the GTPase cycle towards the stalled 'dark state'.

Indexed as

AnimalsAntineoplastic AgentsCarcinoma, Pancreatic DuctalGTP PhosphohydrolasesHEK293 CellsHumansMaleMice, SCIDPancreatic NeoplasmsProtein Tyrosine Phosphatase, Non-Receptor Type 11Proto-Oncogene Proteins p21(ras)raf KinasesXenograft Model Antitumor AssaysAntineoplastic AgentsGTP PhosphohydrolasesKRAS protein, humanProtein Tyrosine Phosphatase, Non-Receptor Type 11Proto-Oncogene Proteins p21(ras)raf Kinases

Identifiers

PMID30644389
PMCPMC6333830
OpenAlexW2909726024

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.