CO-RECEPTOR REGULATION OF TGF-BETA SIGNALING

Transforming growth factor (TGF)-beta superfamily cytokines play integral parts in cell differentiation and proliferation, and their signaling depends on an intricate spatiotemporal orchestration of protein interactions from membrane to nucleus. In general, a TGF-beta ligand binds with a heteromeric receptor complex consisting of type I and type II serine/threonine kinase receptors that activate smad-dependent gene transcription.¹ Rather than a type I/type II receptor combination unique to each ligand, the signaling receptor complexes are composed from a finite group of seven type I (activin-like kinases; ALK) and five type II receptors. This redundancy allows for variation in response depending on ligand presence and/or accessibility. Participating in this regulation are co-receptors, proteins that enable, if not promote, ligand-receptor binding (Figure 1).

Figure 1. Co-receptors interact with TGF-beta ligand and ligand-binding receptor (Type II for TGF-beta 2 and inhibin, Type I for nodal, BMP) to influence cellular response to ligand. A: Obligate co-receptors permit signal transduction by TGF-beta 2. B: Co-receptors for BMP enhance signal, providing increased sensitivity to low BMP concentration.

Betaglycan, also known as TGF-beta RIII, associates with and presents TGF-beta isoforms to the TGF-beta RII (Type II) receptor.² Expression of betaglycan increases the sensitivity of TGF-beta RII-expressing cells to TGF-beta 2 and equalizes the affinities across isoforms,³ thus maximizing TGF-beta signaling. Betaglycan also serves as a prerequisite co-receptor for inhibin,^4,5 a molecule known as an activin antagonist. Inhibin (bound to betaglycan) competitively interacts with activin type II receptors without the recruitment and activation of the type I receptor. Considering that both TGF-beta and activin initiate the smad-2/3 pathway, betaglycan's role as a co-receptor can lead to opposing effects on smad-2/3-dependent processes. TGF-beta signaling specificity is also carried out by endoglin (CD105), a transmembrane glycoprotein expressed on vascular endothelial cells that facilitates TGF-beta 1/3 binding to TGF-beta RII with preferential recruitment of the type I receptor ALK-1.⁶ ALK-1 activates smad-1 and indirectly inhibits TGF-beta/ALK-5/smad-2/3 signaling.⁷ Thus, endoglin appears to moderate a balance between smad-2/3-related cell growth inhibition and smad-1-associated cell proliferation during angiogenesis.⁶

EGF-CFC proteins are essential for vertebrate development by serving as co-receptors for the embryogenesis-related molecules nodal, vitellogenin (Vg)1, and growth differentiation factor (GDF)-1/3.^9-11 The EGF-CFC protein cripto permits nodal signaling by interacting with both ligand (EGF region) and the type I receptor ALK-4 (CFC region) to form a smad-2-activating Act RIIB-ALK 4-nodal-cripto complex. Cripto also can interact with activin/Act RIIB12 and TGF-beta 1/ TGF-beta RII3 complexes, preventing recruitment and activation of their type 1 receptors, ALK-4 and ALK-5, respectively. Cripto's initiation and disruption of TGF-beta signaling highlight mechanisms for its multifunctional role in embryogenesis and tumorigenesis.

Recently, members of the repulsive guidance molecule (RGM) family of GPI-anchored proteins have been identified as specific co-receptors for the BMP subfamily.^14-17 Unlike TGF-beta 2/betaglycan and nodal/cripto, RGM-A-C are not obligate co-receptors for BMP signaling. Rather, they enhance BMP signal transduction through direct interaction with BMP-2/4 and ALK-3/6. This role may provide increased sensitivity to low ligand concentration such as those that may occur in morphogenetic gradients during embryogenesis. This may allow cells to respond at a lower threshold and/or exhibit a greater response. Whether regulation of BMP signaling contributes to RGM-A and RGM-B roles in the developing^18,19 and regenerating²⁰ central nervous system remains to be determined. However, RGM-C (hemojuvelin), as a BMP co-receptor, has been elegantly linked to iron metabolism in vivo and in vitro.¹⁷ Further investigation is necessary to elucidate additional roles for the RGM family in TGF-beta signaling.

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