RACK1, scaffolding a heterotrimeric G protein and a MAPK cascade.
Su Jianbin,Xu Juan,Zhang Shuqun
Trends in plant science
Scaffold proteins of mitogen-activated protein kinase (MAPK) cascades play crucial roles in determining signal specificity, amplitude, and duration in yeast and mammals. Recently, RACK1 was identified as the first plant MAPK scaffold protein that connects heterotrimeric G protein with a MAPK cascade to form a unique signaling pathway in plant immunity.
Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases.
Nature reviews. Rheumatology
Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4(-)CD8(-) (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4(+)CD25(+)FoxP3(+) T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.
Suppression of AMP-activated protein kinase reverses osteoprotegerin-induced inhibition of osteoclast differentiation by reducing autophagy.
Tong Xishuai,Zhang Chuang,Wang Dong,Song Ruilong,Ma Yonggang,Cao Ying,Zhao Hongyan,Bian Jianchun,Gu Jianhong,Liu Zongping
OBJECTIVES:Osteoclasts (OC) are unique terminally differentiated cells whose primary function is bone resorption. We previously showed that osteoprotegerin (OPG) inhibits OC differentiation in vitro by enhancing autophagy via the adenosine monophosphate-activated protein kinase (AMPK)/mTOR/p70S6K signalling pathway in vitro. Here, we aimed to elucidate the mechanism of AMPK mediated autophagy to regulate OPG-mediated inhibition of OC differentiation and identify potential therapeutic targets associated with bone loss. MATERIALS AND METHODS:We used the AMPK activator AICAR to determine the relationship between AMPK activation and OC differentiation, and studied the role of AMPK-mediated autophagy in OPG-mediated inhibition of OC differentiation by using autophagy inhibitors or AMPK knockdown. RESULTS:AMP-activated protein kinase activation caused LC3II accumulation and weakened OC differentiation activity. In contrast, inactivation of autophagy by 3-methyladenine or Bafilomycin A1 could attenuate OPG-mediated inhibition of OC differentiation via the AMPK/mTOR/p70S6K signalling pathway. Furthermore, the AMPK inhibitor compound C and knockdown of AMPK impaired OPG-mediated inhibition of OC differentiation by inducing autophagy. CONCLUSIONS:These results demonstrated that the AMPK signalling pathway functions as a critical regulator in the OPG-mediated inhibition of OC differentiation, by inducing autophagy. Our results provide a basis for future bone-related studies on the AMPK signalling pathway.