Decoding clinical diversity in monogenic TGFBR1 and TGFBR2 mutations: insights into the interplay of molecular mechanisms and hypomorphicity

Figures

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  FIGURE 1. Schematic illustration of canonical and con-canonical TGFβ signaling. Upon ligand binding, TGFBR2 phosphorylates and activates TGFBR1 at specific serine and threonine residues, stabilizing their heterotetrameric structure. Activated TGFBR1 receptors then phosphorylate R-Smads (Smad2 and Smad3), which dimerize and bind to Smad4 to form a trimeric complex. This complex moves to the nucleus and regulates gene expression with other transcription factors. Inhibitory Smads (Smad6 and Smad7) negatively regulate this pathway by preventing R-Smad/Smad4 complex formation and recruiting Smurf1/2, promoting receptor degradation through ubiquitination. On the other hand, TGFBR2 is phosphorylated by SRC, enabling the recruitment of GRB2 and ShcA to activate MAPK signaling. Similarly, TGFBR1 phosphorylates ShcA, forming a ShcA/GRB2/SOS complex that activates Ras, leading to the activation of the MAPK pathway. This figure was generated by Biorender.

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  FIGURE 2. Schematic illustration of TGFBR1 and TGFBR2: Structural Domains and Phosphorylation events. Both receptors possess key functional domains, including extracellular domains, transmembrane domains, and kinase domains. Phosphorylation events occur at different sites; TGFBR2 is autophosphorylated at serine and threonine residues, including Ser213, Ser409, Ser416, Tyr259, Tyr336, Tyr424, and Tyr470, with Tyr284 and Tyr470 being phosphorylated by Src kinase. TGFBR2 phosphorylates TGFBR1 in the GS domain at serine and threonine residues Thr186, Ser187, Ser189, and Ser191. The numbers beside each receptor indicate amino acids. This figure was generated by Biorender.

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  FIGURE 3. Schematic illustration of the molecular mechanisms underlying diseases associated with mutations in TGFBR1 and TGFBR2. Under normal conditions, both alleles of either receptor in a diploid locus are expressed and trafficked to the PM, where they form functional heterotetramers with the other receptor. However, haploinsufficiency occurs when one allele is mutated or deleted, leading to either nonsense-mediated mRNA decay (NMD) of the mutated allele or the proteasomal degradation of the mutant receptor protein, or the trafficking of a non-functional mutant protein to the PM, resulting in a reduction of functional protein into half compared to WT. Dominant-negative effects can further exacerbate HI, as mutant receptor proteins may interfere with WT proteins, either promoting their retention in the ER followed by proteasomal degradation or hindering the formation and function of heterotetramers at the PM, further diminishing overall receptor activity and signaling output. Red: mutated, Purple/Green: either TGFBR1 or 2. This figure was generated by Biorender.