# Signaling mechanisms of the cerebral cavernous malformations protein complex

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $555,030

## Abstract

Multi-PI: Titus J. Boggon and David A. Calderwood
TITLE: Signaling mechanisms of the cerebral cavernous malformations protein complex
ABSTRACT
Loss of function mutations in the genes encoding KRIT1 (CCM1), CCM2 (OSM), or CCM3 (PDCD10) cause
Cerebral Cavernous Malformations (CCM). The presentation of this disease includes dilated leaky blood vessels,
especially in the neurovasculature, resulting in stroke, focal neurological defects, seizures and vascular
abnormalities. Each of the multi-domain CCM proteins functions as a molecular scaffold and importantly, CCM2
recruits the MAP kinase kinase kinase, MEKK3, to the multi-protein CCM signaling complex. Recruitment of
MEKK3 to the CCM complex is thought to result in suppression of MEKK3 activation of the MEK5-ERK5 pathway
and a reduction in KLF2/4 levels. In CCM disease this suppression is lost. Despite extensive research on CCM
proteins and their intersection with MEKK3 major gaps in understanding remain, including 1) the fundamental
organization of the CCM complex and how this impacts its activity, and 2) the mechanisms by which the CCM
complex controls the MEKK3 MAP kinase signaling cascade. In this highly-collaborative, multi-PI proposal the
Boggon and Calderwood laboratories will address these outstanding important gaps in knowledge. We will do
this in two Aims. In Aim 1, building on extensive preliminary data, we propose a revision of canonical models of
the CCM complex and will assess CCM complex stoichiometry as a determinant of signal transduction. In Aim
2, we will discover how CCM proteins act as determinants of MEKK3 signaling outcomes. Our structure-directed
functional studies will reveal the normal formation of and define the basis for targeted CCM complex modulation
of MEKK3-MEK5-ERK5 signaling.

## Key facts

- **NIH application ID:** 10978905
- **Project number:** 1R01NS134606-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Titus Jonathon Boggon
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $555,030
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978905

## Citation

> US National Institutes of Health, RePORTER application 10978905, Signaling mechanisms of the cerebral cavernous malformations protein complex (1R01NS134606-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10978905. Licensed CC0.

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