<b>THE ROLE OF PROTEIN TYROSINE PHOPHATASES (SHP1 AND PTP1B/TCPTP) IN INFLAMMATION AND CANCER</b>

<p dir="ltr">Protein tyrosine phosphatases (PTPs) are critical regulators of cellular signaling, yet their roles in cancer and immune regulation remain incompletely resolved. We addresses two complementary aspects of PTP biology in the regulation of oncogenic ALK signaling by PTP1B and TCPTP, and the functional characterization of a pathogenic SHP1 variant. We investigated the SHP1 A550V mutant, revealing a loss of catalytic function. This result highlights the pathogenic potential of single amino acid substitutions in SHP1, a phosphatase central to hematopoietic and immune homeostasis. The findings establish a framework for systematically expanding functional annotation of SHP1 variants through genomic and mutagenesis screens, with particular relevance to autoimmune, leukemic, and inflammatory disease cohorts. Through substrate-trapping experiments, we demonstrate that NPM1–ALK and STAT1, but not STAT3, are direct substrates of PTP1B and TCPTP in various NPM1-ALK positive cell lines including SU-DHL-1, DEL, SUP-M2, K299. This substrate selectivity defines a previously unrecognized axis of regulation in NPM1-ALK-positive lymphoma. The findings suggest that PTP1B and TCPTP constrain oncogenic kinase activity while selectively modulating downstream transcriptional programs, offering mechanistic insight into their tumor-suppressive roles. Importantly, these results provide a rationale for combination strategies that co-target ALK and phosphatase pathways, with the goal of improving therapeutic depth while preserving STAT1-driven tumor-suppressive signaling. Taken together, the work presented here advances our understanding of PTP biology by illuminating substrate specificity, defining the functional consequences of pathogenic mutation, and identifying therapeutic opportunities at the intersection of oncogenic signaling and immune regulation. These insights provide a mechanistic and translational foundation for the development of precision strategies that exploit PTP biology in NPM1-ALK-driven cancers and SHP1-associated immune disorders.</p>