Fine-Tuning the TGFβ Signaling Pathway by SARA During Neuronal Development

Abstract

Neural development is a complex process that involves critical events, including cytoskeleton dynamics and selective trafficking of proteins to defined cellular destinations. In this regard, Smad Anchor for Receptor Activation (SARA) is an early endosome resident protein, where perform trafficking-associated functions. In addition, SARA is also involved in cell signaling, including the TGFβ-dependent pathway. Accordingly, SARA, and TGFβ signaling are required for proper axonal specification and migration of cortical neurons, unveiling a critical role for neuronal development. However, the cooperative action between the TGFβ pathway and SARA to this process has remained understudied. In this work, we show novel evidence suggesting a cross-talk between SARA and TGFβ pathway needed for proper polarization, axonal specification, growth and cortical migration of central neurons both in vitro and in vivo. Using microscopy tools and cultured hippocampal neurons, we show a local interaction between SARA and TβRI (TGFβ I receptor) at endosomes. In addition, SARA loss of function, induced by the expression of the dominant-negative SARA-F728A, over-activates the TGFβ pathway, most likely by preserving phosphorylated TβRI. Consequently, SARA-mediated activation of TGFβ pathway impacts on neuronal development, promoting axonal growth and cortical migration of neurons during brain development. Moreover, our data suggests that SARA basally prevents the activation of TβRI through the recruitment of the inhibitory complex PP1c/GADD34 in polarizing neurons. Together, these results propose that SARA is a negative regulator of the TGFβ pathway, being critical for a proper orchestration for neuronal development.

Hypoxia Selectively Increases a SMAD3 Signaling Axis to Promote Cancer Cell Invasion

“…One study has shown that the depletion of SARA, or deletion of its SMAD Binding Domain (SBD) in endothelial cells, inhibited the transcriptional activity of both SMAD2 and SMAD3 in vitro [ 84 ], whereas a separate study has shown that SARA depletion in HeLa cells or Mv1Lu cells had little effect on these SMADs [ 64 , 85 ]. SARA was also shown to inhibit SMAD2/3 signaling in rat neural cells [ 86 ]. As alternatives to the targeting of TGFβ or TGFBR per se, different research groups have developed peptide aptamers of SARA SBD that have shown significant inhibition of SMAD2/3 signaling in human renal epithelial cells and mouse mammary gland cells [ 87 , 88 ].…”

Perspectives on Mechanisms Supporting Neuronal Polarity From Small Animals to Humans

“…There is a wide consensus on the classification of these factors into positive and negative signals, promoting or restraining polarization. For instance, BDNF, insulin, IGF-1 and TFG-ß, among others, bind to their plasma membrane receptors triggering activation of intracellular signaling pathways favoring polarization ( Sosa et al, 2006 ; Arimura and Kaibuchi, 2007 ; Yi et al, 2010 ; Nakamuta et al, 2011 ; Takano et al, 2019 ; Rozés-Salvador et al, 2020 ). Most polarizing signals—if not all—are transduced by tyrosine kinase receptors (TRK) located at the plasma membrane, triggering the activation of the phosphatidylinositol 3 kinase (PI3K) and conversion of phosphatidylinositol 4,5 bi-phosphate (PIP2) into phosphatidylinositol 3,4,5 tri-phosphate (PIP3).…”