Dissecting protein tyrosine phosphatase signaling by engineered chemogenetic control of its activity
Year: 2022
Type: article
Abstract: 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.
Source: The Journal of Cell Biology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Awards: G2525931575, Src-mediated pathways regulating adherens junction assembly., Engineered regulation of tyrosine phosphatase activity in living cells, G516062586, Optogenetic tools for the dissection of oncogenic signaling mediated by kinases, G77011330, G9000019790, Training Program in Lung Biology and Pathobiology, Macrophage Plasticity in Inflammatory Lung Injury, G993149817
OpenAlex ID: W4285088502