A Novel Mechanism Involving Four-and-a-half LIM Domain Protein-1 and Extracellular Signal-regulated Kinase-2 Regulates Titin Phosphorylation and Mechanics

被引:83
作者
Raskin, Anna [1 ,2 ]
Lange, Stephan [1 ]
Banares, Katherine [1 ]
Lyon, Robert C. [1 ]
Zieseniss, Anke
Lee, Leonard K. [1 ,2 ]
Yamazaki, Katrina G. [1 ]
Granzier, Henk L. [3 ]
Gregorio, Carol C.
McCulloch, Andrew D. [2 ]
Omens, Jeffrey H. [1 ,2 ]
Sheikh, Farah [1 ]
机构
[1] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA
[3] Univ Arizona, Dept Physiol, Tucson, AZ 85724 USA
基金
美国国家卫生研究院;
关键词
CARDIAC-HYPERTROPHY; PASSIVE TENSION; SKELETAL-MUSCLE; HEART-MUSCLE; EXPRESSION; STIFFNESS; SEQUENCE; COLLAGEN; ACCELERATION; INVOLVEMENT;
D O I
10.1074/jbc.M112.372839
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Understanding mechanisms underlying titin regulation in cardiac muscle function is of critical importance given recent compelling evidence that highlight titin mutations as major determinants of human cardiomyopathy. We previously identified a cardiac biomechanical stress-regulated complex at the cardiac-specific N2B region of titin that includes four-and-a-half LIM domain protein-1 (Fhl1) and components of the mitogen-activated protein signaling cascade, which impacted muscle compliance in Fhl1 knock-out cardiac muscle. However, direct regulation of these molecular components in mediating titin N2B function remained unresolved. Here we identify Fhl1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics. We specifically identify titin N2B as a novel substrate of extracellular signal regulated-kinase-2 (Erk2) and demonstrate that Fhl1 directly interferes with Erk2-mediated titin-N2B phosphorylation. We highlight the critical region in titin-N2B that interacts with Fhl1 and residues that are dependent on Erk2-mediated phosphorylation in situ. We also propose a potential mechanism for a known titin-N2B cardiomyopathy-causing mutation that involves this regulatory complex. These studies shed light on a novel mechanism regulating titin-N2B mechano-signaling as well as suggest that dysfunction of these pathways could be important in cardiac disease states affecting muscle compliance.
引用
收藏
页码:29273 / 29284
页数:12
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