# Obscurin-kinase 1/N-cadherin: a new signaling axis in cardiac structure/function

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $56,369

## Abstract

OBSCN encodes a family of giant, cytoskeletal proteins, obscurins, that play key structural and regulatory
roles in striated muscles. Consistent with this, mutations in OBSCN have been associated with different forms
of cardiomyopathies. Obscurin-B (~870 kDa), the largest known obscurin isoform is a modular protein consisting
of immunoglobulin (Ig) and fibronectin-III (Fn-III) domains followed by an array of tandem signaling motifs and
two COOH-terminal Ser/Thr kinase domains, Kin1 and Kin2 that share ~45% homology with Myosin Light Chain
kinases. Although the presence of Kin1 and Kin2 was discovered almost two decades ago, their enzymatic
activity, catalytic substrates and (patho)physiological roles have remained largely elusive. Recently, our group
demonstrated that both Kin1 and Kin2 are enzymatically active. In particular, Kin1 undergoes autophospho-
rylation and phosphorylates the cytoplasmic domain of N-cadherin. N-cadherin is an essential component of the
adherens junctions (AJ) present in the intercalated disc (ICD), the unique microdomain of the sarcolemma that
mediates the mechanical and electrical coupling of neighboring cardiomyocytes. In view of these findings and
given the coincident distribution of obscurin-B containing Kin1 and N-cadherin at the ICD, we hypothesize that
obscurin-Kin1 plays key roles in cardiomyocyte adhesion and/or communication (at least in part) by modulating
the activities of N-cadherin via phosphorylation of its cytoplasmic domain. We will address this hypothesis by
elucidating the molecular mechanisms that regulate Kin1 activation (Aim 1), determine the role of Kin1-mediated
phosphorylation of N-cadherin in cardiac structure/function (Aim 2), and assessing the impact of a missense
mutation in Kin1 linked to the development of dilated cardiomyopathy (DCM) in humans (Aim 3). During the last
decade, mounting evidence has accumulated, highlighting the intimate involvement of obscurins in cardiac
structure/function in health and the pathogenesis of heart disease when mutated or truncated. Moreover, the
pivotal role of N-cadherin in the mechanical and electrical coupling of adjacent cardiomyocytes has been
extensively documented, although the molecular mechanisms that regulate its functional properties have only
been scantily examined. Our proposal is motivated by this view and will provide important information about the
role of the novel obscurin-Kin1/N-cadherin signaling axis at the ICD in health and how it is compromised in
disease. It will therefore address a fundamental biological question that has translational relevance.

## Key facts

- **NIH application ID:** 11091683
- **Project number:** 3R01HL165634-03S1
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Aikaterini Kontrogianni-Konstantopoulos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $56,369
- **Award type:** 3
- **Project period:** 2022-08-05 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11091683

## Citation

> US National Institutes of Health, RePORTER application 11091683, Obscurin-kinase 1/N-cadherin: a new signaling axis in cardiac structure/function (3R01HL165634-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11091683. Licensed CC0.

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