{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPRY2 is a versatile modulator of receptor tyrosine kinase (RTK) signaling that operates predominantly as a rapid, negative‐feedback inhibitor of the Ras/ERK pathway. Following growth factor stimulation, SPRY2 translocates to the plasma membrane and is phosphorylated, enabling it to bind key adaptor proteins—such as Grb2—to block downstream recruitment of SOS and attenuate mitogenic signals. However, under select conditions its phosphorylation state and interaction with proteins like c‐Cbl can, paradoxically, lead to sustained receptor signaling (by inhibiting receptor ubiquitination and degradation). This dual capability has been documented in developmental systems as well as in tumor cells, indicating that SPRY2 functions as an immediate and context‐dependent modulator of growth factor–induced signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, SPRY2 activity is finely tuned by post‐translational modifications and competitive protein–protein interactions. Its tyrosine and serine phosphorylation—mediated by kinases such as SRC, Mnk1, and DYRK1A—regulates binding to partners like c‐Cbl, CIN85, and even phosphatases that modulate downstream effectors including ERK, AKT, and PTEN. In some contexts, SPRY2 sequesters c‐Cbl to prevent receptor downregulation, while in others, its phosphorylation triggers ubiquitination (via partners like Nedd4) leading to its degradation. Moreover, SPRY2 is targeted by several microRNAs (for example, miR‐21, miR‐27a and members of the miR‐23a/24‐2/27a cluster) and epigenetic alterations, which further shape its impact on signaling cascades that drive cell proliferation, differentiation and migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAltered SPRY2 expression has prominent consequences for cell fate in diverse biological settings. In many cancers—including those of the prostate, colon, liver, lung, pancreas, and even in certain lymphomas—deregulated SPRY2 levels (resulting from gene deletion, promoter hypermethylation or microRNA-mediated silencing) are correlated with either enhanced tumor growth via unchecked Ras/ERK signaling or, contrarily, with a switch to oncogenic signaling modes when receptor degradation is inhibited. In developmental contexts, proper SPRY2 dosage is essential for normal organogenesis (such as palate formation, kidney branching, and cortical patterning) and for controlling differentiation processes including myogenesis and mesenchymal stem cell lineage allocation. Moreover, emerging evidence indicates that abnormal SPRY2 regulation may also impact T-cell function and therapy resistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "27", "end_ref": "41"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "James E Egan, Amy B Hall, Bogdan A Yatsula, et al. 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