ABL2 is a non-receptor tyrosine kinase that functions as a key regulator of cytoskeleton dynamics and cell adhesion. Through tyrosine phosphorylation of substrates including MYH10, CTTN, and tubulins, ABL2 coordinates actin remodeling and directly binds F-actin to regulate cytoskeletal structure [UniProt]. It modulates cell migration and adhesion via phosphorylation of CRK, CRKL, and ARHGAP35, and regulates receptor endocytosis through phosphorylation of receptor tyrosine kinases and endocytic regulators like RIN1 [UniProt]. ABL2 also controls T-cell migration and immune homing through activation of NEDD9/HEF1 and RAP1 [UniProt]. ABL2 plays a critical pathological role in multiple cancers. In Philadelphia chr1-like acute lymphoblastic leukemia (Ph-like ALL), ABL2 rearrangements are among the most common kinase-activating alterations, occurring in 91% of Ph-like ALL cases and activating cytokine-independent proliferation and STAT5 phosphorylation 1. ABL2 fusions are sensitive to dasatinib inhibition 1. In gastric cancer, ABL2 serves as a hub gene promoting tumor progression and M2 macrophage polarization, with elevated expression correlating with poor immunotherapy response 2. ABL2 also drives medulloblastoma leptomeningeal dissemination through c-MYC-dependent pathways 3. During viral infection, HPV16 exploits ABL2 signaling downstream of EGFR for endocytic vesicle maturation during cellular entry 4. Additionally, miR-125a-5p directly targets ABL2 to suppress cervical carcinoma proliferation and migration 5, identifying ABL2 as a therapeutic target in HPV-associated cancers.