{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPragmin was first identified as a novel effector of the small GTPase Rnd2, predominantly expressed in neurons. In this context, Pragmin mediates Rnd2‐dependent activation of RhoA signaling, which in turn regulates actin cytoskeleton reorganization and neurite outgrowth, highlighting its role in neuronal morphology and differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nSubsequent investigations revealed that Pragmin functions as a mammalian EPIYA effector. Tyrosine phosphorylation of its EPIYA motif by Src family kinases enables it to interact specifically with the C-terminal Src kinase (Csk). This interaction sequesters Csk in the cytoplasm, thereby preventing Csk-mediated inactivation of Src kinases. The consequent establishment of a positive feedback loop sustains Src kinase activity, which in turn promotes cell contraction, modifies focal adhesion dynamics, and ultimately impacts processes such as cell adhesion and motility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nStructural and functional studies have further characterized Pragmin as a pseudokinase scaffolding protein. Although its kinase domain adopts a classical protein‐kinase fold, it lacks catalytic activity; instead, its activity is exerted through the recruitment and regulation of other kinases such as Csk. Detailed crystallographic analyses have uncovered that Pragmin’s N- and C-terminal extensions mediate dimerization and higher-order oligomer formation, mechanisms that are critical for its ability to assemble multi-protein signaling complexes. Moreover, Pragmin forms both homotypic and heterotypic associations with related scaffolds (e.g. SgK269/PEAK1), delineating distinct signaling outputs that contribute to oncogenic pathways by modulating growth factor receptor signaling and promoting cell migration. Notably, aberrations in Pragmin-mediated signaling have been implicated in cancer progression, and genetic association studies have identified polymorphisms in the PRAG1 gene as risk factors in conditions such as IgA nephropathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hiroko Tanaka, Hironori Katoh, Manabu Negishi "}, {"type": "b", "children": [{"type": "t", "text": "Pragmin, a novel effector of Rnd2 GTPase, stimulates RhoA activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M511314200"}], "href": "https://doi.org/10.1074/jbc.M511314200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16481321"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16481321"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Fatemeh Safari, Naoko Murata-Kamiya, Yasuhiro Saito, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1107740108"}], "href": "https://doi.org/10.1073/pnas.1107740108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21873224"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21873224"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yoshie Senda, Naoko Murata-Kamiya, Masanori Hatakeyama "}, {"type": "b", "children": [{"type": "t", "text": "C-terminal Src kinase-mediated EPIYA phosphorylation of Pragmin creates a feed-forward C-terminal Src kinase activation loop that promotes cell motility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Sci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cas.12962"}], "href": "https://doi.org/10.1111/cas.12962"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27116701"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27116701"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Carole M Tactacan, Yu Wei Phua, Ling Liu, et al. 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