PIM1 phosphorylates ABI2 to enhance actin dynamics and promote tumor invasion

• Published in: The Journal of cell biology Vol. 222; no. 6; p. 1
• Main Authors: Jensen, Corbin C, Clements, Amber N, Liou, Hope, Ball, Lauren E, Bethard, Jennifer R, Langlais, Paul R, Toth, Rachel K, Chauhan, Shailender S, Casillas, Andrea L, Daulat, Sohail R, Kraft, Andrew S, Cress, Anne E, Miranti, Cindy K, Mouneimne, Ghassan, Rogers, Greg C, Warfel, Noel A
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 05-06-2023
• Subjects: Actin; Actins - genetics; Actins - metabolism; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Biochemistry; Cancer; Cell Line, Tumor; Cell Signaling; Cytoskeleton; Humans; Hypoxia; Kinases; Male; Migration, Motility; Motility; Neoplasm Invasiveness; Phosphorylation; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Proteomics; Proto-Oncogene Proteins c-pim-1 - genetics; Proto-Oncogene Proteins c-pim-1 - metabolism; Signal Transduction; Signaling; Smooth muscle; Substrates; Tumors
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.202208136

Distinguishing key factors that drive the switch from indolent to invasive disease will make a significant impact on guiding the treatment of prostate cancer (PCa) patients. Here, we identify a novel signaling pathway linking hypoxia and PIM1 kinase to the actin cytoskeleton and cell motility. An unbiased proteomic screen identified Abl-interactor 2 (ABI2), an integral member of the wave regulatory complex (WRC), as a PIM1 substrate. Phosphorylation of ABI2 at Ser183 by PIM1 increased ABI2 protein levels and enhanced WRC formation, resulting in increased protrusive activity and cell motility. Cell protrusion induced by hypoxia and/or PIM1 was dependent on ABI2. In vivo smooth muscle invasion assays showed that overexpression of PIM1 significantly increased the depth of tumor cell invasion, and treatment with PIM inhibitors significantly reduced intramuscular PCa invasion. This research uncovers a HIF-1-independent signaling axis that is critical for hypoxia-induced invasion and establishes a novel role for PIM1 as a key regulator of the actin cytoskeleton.