Xenopus Mad Proteins Transduce Distinct Subsets of Signals for the TGFβ Superfamily

Abstract

Xenopus cDNAs homologous to the Drosophila Mad gene and C. elegans CEM genes have been cloned and functionally analyzed by microinjection into frog embryos. The results show that these genes (Xmad) encode intracellular proteins that act downstream of TGF beta superfamily ligands. Most interesting is the fact that different Xmad proteins produce distinct biological responses. Xmad1 produces ventral mesoderm, apparently transducing a signal for BMP2 and BMP4, whereas Xmad2 induces dorsal mesoderm like Vg1, activin, and nodal. These results suggest that an individual Xmad protein waits poised in the cytoplasm for instruction from a distinct subset of TGF beta ligands and then conveys specific information to the nucleus.

Involvement of p21WAF1/Cip1, CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition

“…Therefore, cell type speci®c signaling pathways may be involved in activin A-mediated growth inhibition. The identi®cation of Mad proteins involved in TGFb signaling indeed indicates that the di erent, cytokine speci®c, outcome of signaling, is dependent on the existence of distinct e ector protein species (Gra et al, 1996;Liu et al, 1996b;Hoodless et al, 1996).…”

Smad8B, a Smad8 splice variant lacking the SSXS site that inhibits Smad8‐mediated signalling

“…In Xenopus embryos, Smad1 and Smad2 act to induce ventral mesoderm and dorsal mesoderm, respectively (Baker & Harland 1996;Graff et al 1996;Thomsen 1996), and inhibition of endogenous Smad4 function by a dominant-negative Smad4 results in the perturbation of mesoderm induction (Lagna et al 1996). Smad5 is a closely related gene product of Smad1 (Riggins et al 1996) and mediates a BMP-like signal in Xenopus .…”

Phosphorylation of Ser465 and Ser467 in the C Terminus of Smad2 Mediates Interaction with Smad4 and Is Required for Transforming Growth Factor-β Signaling

“…Whereas Smad1 induces ventral mesoderm, a BMP-like response, Smad2 induces dorsal mesoderm, an activin/TGF-␤-like response (22)(23)(24). Upon ligand stimulation, Smad proteins become phosphorylated on serine and threonine residues (25,26); BMP stimulates Smad1 phosphorylation (12,20,31), whereas TGF-␤ induces Smad2 and Smad3 phosphorylation (17,(27)(28)(29)(30).…”