{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have demonstrated that NPIPB13 functions as a critical negative regulator of receptor tyrosine kinase signaling, particularly influencing HER2 activity. Deregulated HER2 signaling is known to contribute to various pathophysiological conditions, and NPIPB13, acting in a capacity similar to that described for the PEST-type protein-tyrosine phosphatase BDP1, plays an essential role in modulating this pathway. By dephosphorylating HER2 and interfering with the recruitment and phosphorylation of downstream adaptor proteins, NPIPB13 ensures that cellular responses are finely tuned."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \nFunctional studies have revealed that overexpression of NPIPB13 leads to a significant inhibition of ligand-induced activation of HER2, while a reduction in NPIPB13 levels results in increased phosphorylation of HER2. This effect is highly specific; whereas NPIPB13 markedly downregulates HER2 activity, the closely related EGFR is not similarly impacted, underscoring a substrate-specific regulatory mechanism. Furthermore, NPIPB13’s activity extends to the suppression of downstream signaling events, notably by diminishing the phosphorylation of the adaptor protein Gab1 and subsequent activation of the mitogen-activated protein kinase cascade."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \nThe evidence supports a model in which NPIPB13 is coexpressed with HER2 in certain cancer cells, such as those found in breast cancer, suggesting a feedback regulatory role where NPIPB13 attenuates HER2-driven mitogenic signaling. This mechanism presents NPIPB13 as the first protein of its class implicated in directly modulating HER2 signal transduction, thus potentially offering a novel target for therapeutic intervention in diseases where HER2 signaling is aberrant."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Miriam Gensler, Marcus Buschbeck, Axel Ullrich "}, {"type": "b", "children": [{"type": "t", "text": "Negative regulation of HER2 signaling by the PEST-type protein-tyrosine phosphatase BDP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M309527200"}], "href": "https://doi.org/10.1074/jbc.M309527200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14660651"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14660651"}]}]}]}