Activin and TGF-β Signaling: Differential role of a Serine/Threonine phosphatase in the regulation of SMAD2 activity

Abstract

Activins are the most prominent members of the Activin/Inhibin branch of the TGF-and#946; superfamily. Similar to TGF-and#946;, they play an essential role in regulating multiple physiological processes such as development, reproductive physiology, and immune responses. Besides, Activins demonstrate a vital role in wound healing and diseases like fibrosis and cancer. It contributes to various cancer processes, such as cell migration, metastasis, immune evasion, angiogenesis, drug resistance, and cancer cachexia. In recent studies, several differences have been reported between Activin and TGF-and#946; mediated signaling and response. For example, Activins have been shown to function as a morphogen gradient in early embryonic development, unlike TGF-and#61538;and#61472;and are crucial for maintaining pluripotency in embryonic stem cells Despite differences, the primary notion in the field is that Activin signaling mirrors TGF-and#946; signaling, where both the ligands activate the same SMAD2 and SMAD3 proteins and induce similar cellular responses. However, if we look closely at the available literature, it is intriguing that all known TGF-and#946; superfamily ligands (over 40) signal through merely seven type I and five type II receptors and a set of 8 SMAD proteins. This undoubtedly results in a high degree of context-dependent promiscuity, where ligands of one subfamily could signal through receptors of other subfamilies. This could potentially result from additional complexity at the level of signaling, which is poorly understood and represent some of the main standing questions in the field. One of the major non-canonical pathways induced by Activin and TGF-and#946; is ERK/MAPK pathway. The ERK/MAPK pathway forms an essential component of tumorigenesis and is active in most cancers. In addition to being Serine/Threonine kinases, the two TGF-and#946; receptors, type I and type II, also function as tyrosine kinases and undergo auto-phosphorylation at tyrosine residues. These dual-specificity kinases employ various mechanisms to initiate the non-canonical ERK/MAPK pathway; many