KANK2 is a multifunctional regulatory protein that coordinates actin-microtubule dynamics and cell survival. Primarily, KANK2 sequesters nuclear receptor coactivators (NCOA1-3) in the cytoplasm to inhibit transcription 1, and binds talin2 at focal adhesions to stabilize microtubules and regulate actin polymerization critical for cell migration 2. Through Rho signaling pathway interactions with ARHGDIA, KANK2 regulates podocyte migration during kidney development 3. KANK2 also negatively controls apoptosis by sequestering the pro-apoptotic factor AIFM1 in mitochondria; pro-apoptotic stimuli trigger KANK2 proteasomal degradation, releasing AIFM1 to induce apoptosis 4. HSP70 interaction with KANK2 inhibits this apoptotic pathway, protecting against septic lung injury 5. Clinically, reduced KANK2 expression associates with nephrotic syndrome and renal tubular dysfunction; E2F1, TFAP2C, and NRF1 transcription factors positively regulate KANK2 to maintain renal function 6. KANK2 dysregulation appears in multiple disease contexts: it serves as a hub gene in sarcopenia-diabetes pathways 7, is a therapeutic target in neurodegenerative disease 8, and functions as an oncogenic fusion partner in leiomyosarcoma 9. Alternative splicing of KANK2 contributes to hepatocellular carcinogenesis 10.