The gift of Gab

Liu, Yan; Rohrschneider, Larry R.

doi:10.1016/s0014-5793(02)02425-0

Cited by 181 publications

(202 citation statements)

References 67 publications

Supporting

Mentioning

198

Contrasting

Order By: Relevance

“…Beyond the previous report that Gab1 and Gab2 play an important role in the regulation of cardiac function in embryonic development and neonatal mice, 8,9,19 our results demonstrate a novel signaling mechanism underlying pathological stress-induced DCM, in which Gab1 has emerged as a central regulator of adult cardiac function through maintaining mitochondrial integrity and cell survival to protect heart against DCM and heart failure ( Figure 8f). Gab1 plays a crucial role in the normal growth, differentiation and developmental programs, 43 but the physiological and pathological functions of Gab1 in adult animals remain poorly understood. Global Gab1 knockout mice are embryonic lethal and die between e12.5 and e18.5 because of developmental defects in the heart, placenta and integument.…”

Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

View full text Add to dashboard Cite

A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that GabcKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti-and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure. The progression of heart failure is associated with cardiac remodeling, the changes of cardiac structure and function in response to various stress conditions such as pressure overload-generated hemodynamic stress and agingassociated oxidative stress. 1 Under hemodynamic stress, the heart undergoes a stage of compensated hypertrophy and then progresses into decompensated dilated cardiomyopathy (DCM) and heart failure. 2 Cardiac hypertrophy is an adaptive, regulatory process, in which activation of cardiomyocyte survival pathways maintains cardiac homeostasis against external stress. During the transition from compensatory hypertrophy to DCM, cardiomyocyte death plays a critical role in development of heart failure. [3][4][5][6] However, the molecular mechanisms for controlling the balance of cell survival and cell death during cardiac remodeling remain poorly understood.The Grb2-associated binder 1 (Gab1) is a member of the insulin receptor substrate-like multi-substrate docking protein family and expressed in various types of cells, including cardiomyocytes. [7][8][9] It is a central mediator of growth factor receptor signaling. 10,11 Gab1 is phosphorylated by tyrosine kinases, and then phosphorylated Gab1 recruits and activates phosphatidylinositol 3-kinase (PI3K)/Akt and protein tyrosine phosphatase SHP2 (PTPN11)/mitogen-activated protein kinase (MAPK...

show abstract

Section: Resultsmentioning

confidence: 99%

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…These include the Gab1 docking protein as well as the c-Cbl and Cbl-b ubiquitin ligases (Figure 1). Gab1 belongs to a family of docking proteins, including closely related proteins Gab2 and daughter of sevenless , as well as the more remotely related insulin receptor substrate-1, downstream of kinases, and fibroblast growth factor receptor receptor substrate 2 (reviewed in Liu and Rohrschneider, 2002). These proteins lack enzymatic activities.…”

Section: Met Signal Transductionmentioning

confidence: 99%

From Tpr-Met to Met, tumorigenesis and tubes

2007

View full text Add to dashboard Cite

The receptor for hepatocyte growth factor (HGF)/scatter factor (SF), Met, controls a program of invasive epithelial growth through the coordination of cell proliferation and survival, cell migration and epithelial morphogenesis. This process is important during embryogenesis and for organ regeneration in the adult. However, when deregulated the HGF/SF-Met signaling axis contributes to tumorigenesis and metastasis. Studies on the oncogenic activation of the Met receptor have shed light on the molecular mechanisms underlying the oncogenic activation of receptor tyrosine kinase (RTKs). More than a decade ago, work on the Met related oncogene, Tpr-Met, revealed the mechanism for activation of RTK-derived oncogenes generated following chromosomal translocation. More recently, studies on the mechanisms of downregulation of the Met RTK highlight a role for loss of downregulation in RTK oncogenic activation.

show abstract

“…It was recently recognized that scaffolding adapter proteins might play critical roles in coupling/amplifying signals emanating from growth factor receptors and, in particular, accumulating experimental data suggest a putative role of Gab2 in Neu-induced breast cancer. Like other Gab family members, Gab2 possesses a pleckstrin homology PH domain at the N-terminus, proline-rich motifs, and multiple tyrosine residues that couple with SH2-containing molecules, in a phosphorylation-dependent manner (Liu and Rohrschneider, 2002;Gu and Neel, 2003). Elevated expression of Gab2 has been found in human primary breast cancer specimens and cell lines (Daly et al, 2002).…”

Section: Introductionmentioning

confidence: 99%