TGF-beta 2 (Transforming Growth Factor beta 2) is one of three closely related mammalian
members of the large TGF-beta superfamily that share a characteristic cysteine knot structure
(1-7). TGF-beta 1, 2 and 3 are encoded by separate genes, but are often called isoforms. They are
highly pleiotropic cytokines that are proposed to act as cellular switches regulating processes
such as immune function, proliferation and epithelial-mesenchymal transition (4-8).
Mammalian TGF-beta 2 is secreted as a 395 amino acid (aa) proprotein that is processed by a
furin-like convertase to generate an N-terminal latency-associated peptide (LAP, ~232 aa) and
a C-terminal mature TGF-beta 2 (~112 aa) that remain associated via hydrogen bonding (9-13).
Serine proteases such as plasmin, matrix metalloproteases, or thrombospondin-1, along with
cofactors such as certain integrins, can dissociate LAP and release active TGF-beta 2 (11-14). In
many types of cells, latent TGF-beta binding protein (LTBP) is covalently linked to the LAP
homodimer prior to secretion. LTBP creates a large latent complex that is secreted, but may
bind and localize to the extracellular matrix (10, 11). For TGF-beta isoforms, the latency
components act as natural antagonists of TGF-beta activity, target TGF-beta to distinct tissues, and
maintain a reservoir of TGF-beta (1). Mature mouse and rat TGF-beta 2 share 100% aa sequence
identity, and share 97% aa identity with human, porcine, canine, equine and bovine TGF-beta 2.
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).