TGF-beta 2 signaling begins with binding to a complex of the accessory receptor betaglycan (also
known as TGF-beta RIII) and the TGF-beta RII type II ser/thr kinase receptor (15). In contrast, TGF-beta 1
and 3 have higher affinity for TGF-beta RII and do not require betaglycan (15). TGF-beta RII then
phosphorylates and activates another ser/thr kinase receptor, TGF-beta RI (also called activin
receptor-like kinase (ALK) -5), or alternatively, ALK-1. The whole complex phosphorylates and
activates Smad proteins that regulate transcription (1, 6, 15, 16). Differences in structure of the
prodomains and mature sequences of TGF-beta isoforms, and use of Smad-independent signaling
pathways, allow for disparate actions observed in response to different TGF-beta isoforms and
contexts (1-3, 12, 13, 15, 16).
Although many functions are overlapping, each TGF-beta isoform has some non-redundant
functions. TGF-beta 2 plays a non-redundant role in human and mouse developmental heart valve
remodeling, and mice with targeted deletions of TGF-beta 2 show defects in development of the
cardiac system as well as lung, craniofacial, limb, eye, ear and urogenital systems (2, 7, 17, 28).
TGF-beta 2 plays a unique positive regulatory role in hematopoiesis by enhancing Flt-3 signaling in
hematopoietic progenitors (19). In humans, TGF-beta isoforms, especially TGF-beta 2, are identified as
key factors in the progression of malignant glioma, gastric and ovarian cancer (8, 20-22).
TGF-beta isoforms, particularly TGF-beta 2, suppress macrophage cytokine production and mucosal
inflammatory responses in the developing intestine (23). In turn, macrophage LRP-1 can
downregulate expression of TGF-beta 2 during vascular remodeling, which suppresses neo-intima
formation (24).
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