Insulin receptor substrate 4 (IRS4)

Insulin receptor substrate 4 (IRS4) is a cytoplasmic scaffold/adaptor protein that mediates signal transduction from various growth factor receptors with tyrosine kinase activity, including the insulin receptor, IGF1R, and FGFR1[4][5]. It contains pleckstrin homology (PH) and phosphotyrosine-binding (PTB) domains, followed by a C-terminal region with multiple phosphorylation sites[1][2]. Unlike other IRS family members, IRS4 can activate the PI3K/Akt pathway constitutively, independent of upstream signals and without canonical feedback inhibition, making it a potent oncogenic driver and a cause of resistance to HER2-targeted therapies such as trastuzumab and lapatinib in breast cancer[3]. IRS4 also functions in modulating Jak/STAT signaling (by binding to USP18 and modulating host immunity[1]) and can interact with the BMP receptor BMPRII to repress BMP/Smad signaling and promote myogenic differentiation via Akt activation[2]. IRS4 exhibits tissue-specific expression, notably in brain, kidney, and muscle, and its dysregulation is associated with several cancers and resistance phenotypes[3].

Other names

IRS-4py160pp160PY160160 kDa phosphotyrosine proteinphosphoprotein of 160 kDaCHNG9

In the context of resistance, HER2-targeted therapies (e.g., trastuzumab, lapatinib) are less effective due to IRS4-mediated constitutive activation of the PI3K/Akt pathway[3].