dAKAP1 and Cancer Progression

A positive prognosis for breast cancer is less certain when primary tumors metastasize.  Many signaling pathways that converge on mitochondrial function are engaged during metastasis.  Through screening of deidentified cancer patient databases we have detected an inverse relationship between the expression of outer mitochondrial membrane associated anchoring protein dAKAP1 and breast cancer.  Genetic depletion of dAKAP1–PKA “signaling islands” from the outer mitochondrial membrane augments progression toward metastatic breast cancer.  Mass spectrometry, RNA seq and biochemical analyses now show that dAKAP1 anchors additional components including kinases, phosphatase, the ribonucleoprotein granule proteins LARP4 and PABPC1. We postulate that local translation of mRNAs at the outer mitochondrial membrane is a means to spatially control the synthesis of proteins that contribute to the changes in mitochondrial metabolism during a progression towards metastasis.  

 
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Aggarwal-Howarth, S., Gabrovsek, L., Langeberg, L.K., Golkowski, M., Ong, S., Smith, F.D., and Scott, J.D. (2018) Depletion of dAKAP-1-signaling islands during breast cancer metastasis accompanies pathological changes in mitochrondrial dynamics. J Biol Chem. 294(9):3152-3168.  PMC6398132

Gabrovsek L, Collins KB, Aggarwal S, Saunders LM, Lau HT, Suh D, Sancak Y, Trapnell C, Ong SE, Smith FD, Scott JD. (2020) A-kinase-anchoring protein 1 (dAKAP1)-based signaling complexes coordinate local protein synthesis at the mitochondrial surface. J Biol Chem 295(31):10749-10765.: PMC7397098