Structural and mechanistic basis of protein tyrosine phosphatase regulation by CABIT family proteins in immune signalling (360G-Wellcome-337830_Z_25_Z)

Immune signalling is tightly controlled by phosphorylation, balanced by the opposing activities of kinases and protein tyrosine phosphatases (PTPs). Efforts to therapeutically target PTPs have been hindered by poor specificity and efficacy, and an incomplete understanding of their regulatory networks. CABIT proteins are an evolutionarily conserved but largely uncharacterised family of cytosolic adapters proteins. CABIT proteins, including Themis in T cells and Themis2 in macrophages, engage PTPs such as SHP-1, but how these assemblies modulate PTP activity is unresolved. My previous work elucidated the first structure of a CABIT protein, revealing how Themis assembles a signalling hub to regulate SHP-1 after T cell activation. Building on this foundation, I hypothesise that CABIT proteins act as conserved regulators of PTPs across immune lineages. I will integrate structural biology, molecular immunology and in vivo models to: (1) Structurally and functionally characterise Themis-SHP-1 complexes in T cell signalling (2) Discover regulatory peptides against SHP-1 and the related enzyme SHP-2 (3) Investigate Themis2-SHP-1 complexes in macrophages. This work will establish CABIT proteins as a new class of PTP regulators across innate and adaptive immunity during cancer, infection and tissue repair and will provide the structural framework for selective targeting of SHP-1.