Calcium and Calmodulin-dependent Serine/Threonine Protein Kinase Type II (CaMKII)-mediated Intramolecular Opening of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP-1α) Negatively Regulates β1 Integrins

Millon‐Frémillon, Angélique; Brunner, Molly; Abed, Nadia; Collomb, Elodie; Ribba, Anne-Sophie; Block, Marc R.; Albiges-Rizo, Corinne; Bouvard, Daniel

doi:10.1074/jbc.m113.455956

Cited by 19 publications

(21 citation statements)

References 50 publications

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“…It has been suggested that ICAP1 can adopt a closed conformation where the N-terminal and C-terminal portions of the protein associate, masking the integrinbinding site in the ICAP1 PTB domain (38). Deletion of the ICAP1 N-terminal region might disrupt the inhibitory closed conformation, resulting in increased integrin binding, and this could explain why the ICAP1 PTB is a more potent inhibitor of ␤1 integrin activation than ICAP1 FL .…”

Section: Resultsmentioning

confidence: 99%

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Draheim

Huet-Calderwood

Simon

et al. 2017

Journal of Biological Chemistry

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Edited by Thomas SöllnerBinding of ICAP1 (integrin cytoplasmic domain-associated protein-1) to the cytoplasmic tails of ␤1 integrins inhibits integrin activation. ICAP1 also binds to KRIT1 (Krev interaction trapped-1), a protein whose loss of function leads to cerebral cavernous malformation, a cerebrovascular dysplasia occurring in up to 0.5% of the population. We previously showed that KRIT1 functions as a switch for ␤1 integrin activation by antagonizing ICAP1-mediated inhibition of integrin activation. Here we use overexpression studies, mutagenesis, and flow cytometry to show that ICAP1 contains a functional nuclear localization signal and that nuclear localization impairs the ability of ICAP1 to suppress integrin activation. Moreover, we find that ICAP1 drives the nuclear localization of KRIT1 in a manner dependent upon a direct ICAP1/KRIT1 interaction. Thus, nuclear-cytoplasmic shuttling of ICAP1 influences both integrin activation and KRIT1 localization, presumably impacting nuclear functions of KRIT1.

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Section: Resultsmentioning

confidence: 99%

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Draheim

Huet-Calderwood

Simon

et al. 2017

Journal of Biological Chemistry

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“…Interaction between endothelial cells and basement membrane induces β1-integrin engagement, increases MLC phosphorylation in an MLC kinase and ROCK -dependent fashion to promote claudin-5, occludin, and ZO-1 reorganization at the cell-cell junction [137]. This pathway is likely affected by CCM proteins through KRIT1 binding to the β1-integrin signaling inhibitor ICAP-1, a protein that can also bind to ROCK [138][139][140]. The KRIT1 binding small GTPase Rap1 enhances tight junction protein localization at endothelial cell-cell contact sites and promotes endothelial barrier function [141].…”

Section: Tight Junctions and Ccm Diseasementioning

confidence: 99%

Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation

Wei

Polster

et al. 2020

IJMS

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Cerebral cavernous malformation (CCM) is a disease characterized by mulberry shaped clusters of dilated microvessels, primarily in the central nervous system. Such lesions can cause seizures, headaches, and stroke from brain bleeding. Loss-of-function germline and somatic mutations of a group of genes, called CCM genes, have been attributed to disease pathogenesis. In this review, we discuss the impact of CCM gene encoded proteins on cellular signaling, barrier function of endothelium and epithelium, and their contribution to CCM and potentially other diseases.

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“…KRIT1 has also been shown to interact with ICAP1, a small 200 amino acid protein that encodes a short N-terminal region that can be phosphorylated by CaMKII [74] and a C-terminal PTB domain [75]. The PTB domain of ICAP1 has long been thought to directly interact with integrin cytoplasmic tails [75-78].…”

Section: Ccm Proteins and Their Involvement In Cellular Pathwaysmentioning

confidence: 99%

“…Because it was believed to compete with talin, the master regulator of integrin activation, ICAP1 was thought to be an integrin suppressor [79-81], and this was recently clearly demonstrated [42]. ICAP1 is also a known binder of KRIT1 [35, 82], and was thought to sequester ICAP1 away from integrin tails, allowing talin- and kindlin-mediated activation [74, 79, 80, 83]. Recent structural work has revealed that KRIT1 and integrin β1 directly compete for binding to ICAP1 by its PTB domain, and that both the first KRIT1 NPxY/F motif and the integrin β1 NPxY motif occupy the same binding site on ICAP1 [42].…”

Section: Ccm Proteins and Their Involvement In Cellular Pathwaysmentioning

confidence: 99%

Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

Fisher

Boggon

2013

Cell. Mol. Life Sci.

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Cerebral cavernous malformations (CCM) are neurovascular dysplasias that result in mulberry-shaped lesions predominantly located in brain and spinal tissues. Mutations in three genes are associated with CCM. These genes encode for the proteins KRIT1/CCM1 (krev interaction trapped 1/cerebral cavernous malformations 1), cerebral cavernous malformations 2, osmosensing scaffold for MEKK3 (CCM2/malcavernin/OSM), and cerebral cavernous malformations 3/programmed cell death 10 (CCM3/PDCD10). There have been many significant recent advances in our understanding of the structure and function of these proteins, as well as in their roles in cellular signaling. Here, we provide an update on the current knowledge of the structure of the CCM proteins and their functions within cellular signaling, particularly in cellular adhesion complexes and signaling cascades. We go on to discuss subcellular localization of the CCM proteins, the formation and regulation of the CCM complex signaling platform, and current progress towards targeted therapy for CCM disease. Recent structural studies have begun to shed new light on CCM protein function, and we focus here on how these studies have helped inform the current understanding of these roles and how they may aid future studies into both CCM-related biology and disease mechanisms.

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Calcium and Calmodulin-dependent Serine/Threonine Protein Kinase Type II (CaMKII)-mediated Intramolecular Opening of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP-1α) Negatively Regulates β1 Integrins

Cited by 19 publications

References 50 publications

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences β1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus

Cerebral Cavernous Malformation Proteins in Barrier Maintenance and Regulation

Signaling pathways and the cerebral cavernous malformations proteins: lessons from structural biology

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