Smad3 Couples Pak1 With the Antihypertrophic Pathway Through the E3 Ubiquitin Ligase, Fbxo32.
Pathological cardiac hypertrophy is regarded as a critical intermediate step toward the development of heart failure. Many signal transduction cascades are demonstrated to dictate the induction and progression of pathological hypertrophy; however, our understanding in regulatory mechanisms responsible for the suppression of hypertrophy remains limited. In this study, we showed that exacerbated hypertrophy induced by pressure overload in cardiac-deleted Pak1 mice was attributable to a failure to upregulate the antihypertrophic E3 ligase, Fbxo32, responsible for targeting proteins for the ubiquitin-degradation pathway. Under pressure overload, cardiac overexpression of constitutively active Pak1 mice manifested strong resilience against pathological hypertrophic remodeling. Mechanistic studies demonstrated that subsequent to Pak1 activation, the binding of Smad3 on a critical singular AGAC(-286)-binding site on the FBXO32 promoter was crucial for its transcriptional regulation. Pharmacological upregulation of Fbxo32 by Berberine ameliorated hypertrophic remodeling and improved cardiac performance in cardiac-deficient Pak1 mice under pressure overload. Our findings discover Smad3 and Fbxo32 as novel downstream components of the Pak1-dependent signaling pathway for the suppression of hypertrophy. This discovery opens a new venue for opportunities to identify novel targets for the management of cardiac hypertrophy.
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Hoyee
H
Tsui
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Min
M
Zi
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Shunyao
S
Wang
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Sanjoy K
SK
Chowdhury
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Sukhpal
S
Prehar
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Qiangrong
Q
Liang
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Elizabeth J
EJ
Cartwright
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.).
Ming
M
Lei
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.). xin.wang@manchester.ac.uk wei.liu@manchester.ac.uk.
Wei
W
Liu
From the Faculty of Life Sciences (H.T, S.W., S.K.C., W.L., X.W.) and Faculty of Medical and Human Sciences (M.Z., S.P., E.J.C.), University of Manchester, Manchester, United Kingdom; Department of Biomedical Sciences, New York Institute of Technology, NY (Q.L.); and Department of Pharmacology, University of Oxford, Oxford, United Kingdom (M.L.). xin.wang@manchester.ac.uk wei.liu@manchester.ac.uk.
Xin
X
Wang
D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000473:pathology; D001599:Berberine / Q000494:pharmacology; D006332:Cardiomegaly / Q000235:genetics / Q000517:prevention & control; D002478:Cells, Cultured; D003251:Constriction, Pathologic; D015151:Immunoblotting; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
D009124:Muscle Proteins; D051900:Smad3 Protein; D001599:Berberine; C486692:Fbxo32 protein, rat; D044843:SKP Cullin F-Box Protein Ligases; D054462:p21-Activated Kinases
Fbxo32 protein, mouse; Smad3 protein; hypertrophy; p21-activated kinases; ubiquitin