New Player in Endosomal Trafficking: Differential Roles of Smad Anchor for Receptor Activation (SARA) Protein

Abstract

The development and maintenance of multicellular organisms require specialized coordination between external cellular signals and the proteins receiving stimuli and regulating responses. A critical role in the proper functioning of these processes is played by endosomal trafficking, which enables the transport of proteins to targeted sites as well as their return to the plasma membrane through its essential components, the endosomes. During this trafficking, signaling pathways controlling functions related to the endosomal system are activated both directly and indirectly. Although there are a considerable number of molecules participating in these processes, some are more known than others for their specific functions. Toward the end of the 1990s, Smad anchor for receptor activation (SARA) protein was described to be controlling and to facilitate the localization of Smads to transforming growth factor β (TGF-β) receptors during TGF-β signaling activation, and, strikingly, SARA was also identified to be one of the proteins that bind to early endosomes (EEs) participating in membrane trafficking in several cell models. The purpose of this review is to analyze the state of the art of the contribution of SARA in different cell types and cellular contexts, focusing on the biological role of SARA in two main processes, trafficking and cellular signaling, both of which are necessary for intercellular coordination, communication, and development.

Neuronal Polarity: Positive and Negative Feedback Signals

“…In the developing cortex, neurons are surrounded by specific microenvironments containing extracellular molecules such as neurotrophins [brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT3)], insulin-like growth factor 1 (IGF1), Wnt5A, transforming growth factor-β (TGF-β) and Semaphorin 3A, and cell adhesion molecules such as TAG1 and N-cadherin, which provide cues for neuronal polarization (Figure 2A; Funahashi et al, 2014; Namba et al, 2015; Takano et al, 2015; Rozes-Salvador et al, 2018). Indeed, inhibition of neurotrophin receptors, TrkB and TrkC, block the MP-to-BP transition in vivo (Nakamuta et al, 2011).…”

“…The phospho-mimic mutant of Par3, which cannot bind to KIF3A, failed to rescue the knockdown phenotype, indicating that the accumulation of Par3 in the nascent axon is essential for MP-to-BP transition in vivo (Funahashi et al, 2013). Par6 also colocalizes with the TGF-β receptor (TβR2) and the phosphorylation of Par6 at Ser345 by the TGF-β receptor regulates axon formation and neuronal migration (Ozdamar et al, 2005; Yi et al, 2010; Rozes-Salvador et al, 2018).…”

The Genomic Response to TGF-β1 Dictates Failed Repair and Progression of Fibrotic Disease in the Obstructed Kidney

“…C-terminal SxS motif (Ser 423/425 and Ser 465,467 for SMAD3 and SMAD2, respectively) (Matsuzaki, 2013). While early models suggested that SMAD2 interacts with the SMAD binding domain (SBD) of the SMAD anchor for receptor activation (SARA) followed by SARA:SMAD2 delivery to the TGF-βRI via the C-terminal domain of SARA to facilitate R-SMAD phosphorylation, the actual involvement of SARA in TGF-β signaling is controversial (Rozés-Salvador et al, 2018. Regardless of the precise mechanism, pR-SMADs complex with the shuttle SMAD4 and translocate to the nucleus to impact transcription of a rather large slate of TGF-β1 responsive genes (Massagué, 2000;Massague, 2012).…”

AGAP2: Modulating TGFβ1-Signaling in the Regulation of Liver Fibrosis

“…The role played by this protein in TGFRs trafficking and TGFβ1 signaling remains controversial, and its expression tends to decrease in liver fibrosis. All these aspects have been recently reviewed by Rozés-Salvador et al in [58].…”