Figure 1.

Canonical and non-canonical SMAD5 signaling. (A) Canonical activation of SMAD5 occurs preferentially upon binding of the TGF-β-related ligands to their cognate receptor kinases. Upon ligand binding, type I and type II receptors form activated, heterotetrameric receptor complexes. Activated type I receptors recruit and phosphorylate SMAD5 on two Ser residues. Two phospho-SMAD5s then assemble as a trimer with SMAD4 and translocate into the nucleus, where they associate with assorted transcription factors and cofactors as well as chromatin-modifying and -remodeling complexes that activate or repress expression of target genes. (B) Non-canonical cytoplasmic signaling of SMAD5 occurs in response to environmental cues (e.g., temperature, pHe and osmolality) and potentially other stimuli that acutely increase cytoplasmic pHc, causing net accumulation of unphosphorylated SMAD5 in the cytoplasm. The more alkaline pHc promotes binding of SMAD5 to HK1, which in turn enhances the rate of glycolysis.