Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity

Fauser, Jordan; Huyot, Vincent; Matsche, Jacob; Szynal, Barbara N.; Alexeev, Yuri; Kota, Pradeep; Karginov, Andrei V.

doi:10.1083/jcb.202111066

Title: Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity

Journal Article · 13 July 2022 · Journal of Cell Biology

DOI: https://doi.org/10.1083/jcb.202111066 · OSTI ID:1875934

; Huyot, Vincent;

; Szynal, Barbara N.;

;

Protein tyrosine phosphatases (PTPases) are critical mediators of dynamic cell signaling. A tool capable of identifying transient signaling events downstream of PTPases is essential to understand phosphatase function on a physiological time scale. We report a broadly applicable protein engineering method for allosteric regulation of PTPases. This method enables dissection of transient events and reconstruction of individual signaling pathways. Implementation of this approach for Shp2 phosphatase revealed parallel MAPK and ROCK II dependent pathways downstream of Shp2, mediating transient cell spreading and migration. Furthermore, we show that the N-SH2 domain of Shp2 regulates MAPK-independent, ROCK II-dependent cell migration. Engineered targeting of Shp2 activity to different protein complexes revealed that Shp2-FAK signaling induces cell spreading whereas Shp2-Gab1 or Shp2-Gab2 mediates cell migration. We identified specific transient morphodynamic processes induced by Shp2 and determined the role of individual signaling pathways downstream of Shp2 in regulating these events. Broad application of this approach is demonstrated by regulating PTP1B and PTP-PEST phosphatases.

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Research Organization:: Argonne National Laboratory (ANL), Lemont, IL (United States)

Sponsoring Organization:: National Institute of Health; USDOE; USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1875934

Journal Information:: Journal of Cell Biology, Journal Name: Journal of Cell Biology Journal Issue: 8 Vol. 221; ISSN 0021-9525

Publisher:: Rockefeller University PressCopyright Statement

Country of Publication:: United States

Language:: English

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Title: Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity

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