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Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer

Research Project
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01.09.2019
 - 01.09.2022

Phosphatidyl-inositol 3,4,5 triphosphoshate-dependent Rac exchanger (P-Rex) are a group of proteins involved in the activation of the small GTPase Rac, by acting as a guanidine exchange factor (GEF). Both Rac and P-Rex proteins are known to be overexpressed and altered in several cancers, consistent with their role in both cell mobility and their numerous interactions with both the mTOR axis and the PI3K/PTEN pathway. P-Rex1/2 specifically, are known to interact with mTOR and PTEN, among others, placing them at the nexus of regulatory pathways for cell metabolism, proliferation and mobility.Despite their central role in cell signaling, very little is known about the interplay between such interactions. No structural information is available for the full-length P-Rex proteins and how different interaction partners affect its structure and function. I will therefore set out to better characterize the emerging properties of the multidomain P-Rex proteins by purifying both P-Rex1/2 and determining their structure using cryo-EM and orthogonal biophysical characterization methods. I then aim to define the interaction between P-Rex proteins and its regulatory partners, PTEN and the mTOR complexes 1 and 2. I will define their domains of interactions and determine the structure of the complexes, using a combination of cryo-EM and cross-linking and mass-spectrometry. We expect to provide new insights into the functions of P-Rex proteins and their crosstalk with core cellular signaling pathways. Structures of full-lengths P-Rex alone or in complex with its interaction partners will serve as a platform for drug discovery, thereby providing new cancer therapeutic avenues

Funding

Structural and functional characterization of P-Rex 1/2 in cell signaling and cancer

Weitere ausländische Förderagenturen (GrantsTool), 09.2019-09.2022 (37)
PI : Chaker-Margot, Malik,Maier, Timm.

Members (2)

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Timm Maier

Principal Investigator
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Malik Chaker-Margot

Principal Investigator