Abstract
The mitogen activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) pathway is a central downstream signaling pathway that is activated in cardiac muscle cells during mechanical and agonist-mediated hypertrophy. Studies in genetic mouse models deficient in ERK-associated MAPK components pathway have further reinforced a direct role for this pathway in stress-induced cardiac hypertrophy and disease. However, more recent studies have highlighted that these signaling pathways may exert their regulatory functions in a more compartmentalized manner in cardiac muscle. Emerging data has uncovered specific MAPK scaffolding proteins that tether MAPK/ERK signaling specifically at the sarcomere and plasma membrane in cardiac muscle and show that deficiencies in these scaffolding proteins alter ERK activity and phosphorylation, which are then critical in altering the cardiac myocyte response to stress-induced hypertrophy and disease progression. In this review, we provide insights on ERK-associated scaffolding proteins regulating cardiac myofilament function and their impact on cardiac hypertrophy and disease.
Highlights
The mitogen activated protein kinase (MAPK)-extracellular regulated kinase 1/2 (ERK1/2) pathway is a central downstream signaling pathway that is activated in cardiac muscle cells during mechanical and agonist-mediated hypertrophy
In Four and a Half LIM Domain Protein-1 (FHL1) deficient settings, a unique role for the MAPK component, ERK2, was identified as it was no longer tethered to titin N2B but instead “open” to directly phosphorylate titin N2B to increase compliance of cardiac muscle as opposed to being sequestered to participate in hypertrophic signaling (Raskin et al, 2012). These results suggest that FHL1 functions as a MAPK scaffold by directly interacting with Raf-1/MEK2/ ERK2 to physically insulate the MAPK pathway to the titin N2B region of the sarcomere in a Gq stimulus-specific manner and efficiently transmit MAPK signals to regulate cardiac hypertrophy (Figure 1)
In mouse models deficient in MAPK scaffold proteins bound to the sarcomere, such as FHL1 and Ankyrin Repeat Domain 1 (ANKRD1), suggest a detrimental role in Gαq and phenylephrine-induced cardiac hypertrophy, respectively, while studies on MAPK scaffold proteins bound to the plasma membrane, such as IQGAP1 and Sur-8, suggest a protective role in mechanical induced-cardiac hypertrophy
Summary
Reviewed by: Bin-Nan Wu, Kaohsiung Medical University, Taiwan Claudia Penna, University of Torino, Italy. Specialty section: This article was submitted to Cardiovascular and Smooth Muscle. Received: 19 December 2015 Accepted: 11 February 2016 Published: 29 February 2016
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