LIMD1 phosphorylation in mitosis is required for mitotic progression and its tumor-suppressing activity.

Abstract

LIM domains containing 1 (LIMD1) is a member of the Zyxin family proteins and functions as a tumor suppressor in lung cancer. LIMD1 has been shown to regulate Hippo-YAP signaling activity. Here, we report a novel regulatory mechanism for LIMD1. We found that cyclin-dependent kinase 1 (CDK1) and c-Jun NH2-terminal kinases 1/2 (JNK1/2) phosphorylate LIMD1 invitro and in cells during anti-tubulin drug-induced mitotic arrest. Phosphorylation also occurs during normal mitosis. S272, S277, S421, and S424 were identified as the main phosphorylation sites in LIMD1. Deletion of LIMD1 resulted in a shortened mitotic cell cycle and phosphorylation of LIMD1 is required for proper mitotic progression. We further showed that the phosphorylation-deficient mutant LIMD1-4A is less active in suppressing cell proliferation, anchorage-independent growth, cell migration, and invasion in lung cancer cells. Together, our findings suggest that LIMD1 is a key regulator of mitotic progression, and that dysregulation of LIMD1 contributes to tumorigenesis.