Serine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation

Research output: Contribution to journalArticle


External Institution(s)

  • Yale University


Original languageEnglish (US)
Pages (from-to)3269-3284
Number of pages16
JournalJournal of Biological Chemistry
Issue number10
StatusPublished - Mar 6 2020


Nuclear accumulation of the small phosphoprotein integrin cytoplasmic domain-associated protein-1 (ICAP1) results in recruitment of its binding partner, Krev/Rap1 interaction trapped-1 (KRIT1), to the nucleus. KRIT1 loss is the most common cause of cerebral cavernous malformation, a neurovascular dysplasia resulting in dilated, thin-walled vessels that tend to rupture, increasing the risk for hemorrhagic stroke. KRIT1's nuclear roles are unknown, but it is known to function as a scaffolding or adaptor protein at cell-cell junctions and in the cytosol, supporting normal blood vessel integrity and development. As ICAP1 controls KRIT1 subcellular localization, presumably influencing KRIT1 function, in this work, we investigated the signals that regulate ICAP1 and, hence, KRIT1 nuclear localization. ICAP1 contains a nuclear localization signal within an unstructured, N-terminal region that is rich in serine and threonine residues, several of which are reportedly phosphorylated. Using quantitative microscopy, we revealed that phosphorylation-mimicking substitutions at Ser-10, or to a lesser extent at Ser-25, within this N-terminal region inhibit ICAP1 nuclear accumulation. Conversely, phosphorylation-blocking substitutions at these sites enhanced ICAP1 nuclear accumulation. We furtherdemonstratethatp21-activatedkinase4(PAK4)canphosphorylate ICAP1 at Ser-10 both in vitro and in cultured cells and that active PAK4 inhibits ICAP1 nuclear accumulation in a Ser-10 - dependent manner. Finally, we show that ICAP1 phosphorylation controls nuclear localization of the ICAP1-KRIT1 complex. We conclude that serine phosphorylation within the ICAP1 N-terminal region can prevent nuclear ICAP1 accumulation, providing a mechanism that regulates KRIT1 localization and signaling, potentially influencing vascular development.

Citation formats


Su, V. L., Simon, B., Draheim, K. M., & Calderwood, D. A. (2020). Serine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation. Journal of Biological Chemistry, 295(10), 3269-3284.


Su, VL, Simon, B, Draheim, KM & Calderwood, DA 2020, 'Serine phosphorylation of the small phosphoprotein ICAP1 inhibits its nuclear accumulation', Journal of Biological Chemistry, vol. 295, no. 10, pp. 3269-3284.