TGF-β Signaling Mechanisms
The TGF-β receptor complex differs from those depicted in Figure 16.9 in that, while having a cytoplasmic protein kinase domain, the specificity for this protein kinase is not tyrosine but serine/threonine. Furthermore, there are two types of TGF-β receptors, and interaction with the ligand requires an interaction with each of the two types, type 1 and type 2. Since type 2 recep- tors may bind ligand directly from the medium while type 1 receptors cannot, it is likely that the final complex involves a heterotetramer in which the type 1 receptor may differ depending on the member of the TGF-β family involved (cf. Ruscetti et al., 1998). A diagram indicating the interaction with TGF-β and the two forms of the receptor as a heterotetramer with activation of the kinase domain is seen in Figure 16.13. For this signal transduction pathway, a different series of downstream signaling molecules known as Smad proteins are involved, with a series of phos- phorylations, as noted in the figure, ultimately resulting in an activated complex of Smad pro- teins that may associate with transcription factors and activate DNA transcription of specific genes (Visser and Themmen, 1998).
Influences of Growth Factors on Cell Transformation
Prior to the discovery of transforming growth factors, there was a general belief that cells pro- ducing hormones or growth factors did not possess receptors for the hormone or growth factor produced by the cell itself. The secretion by such cells of endocrine glands was termed endo- crine secretion. Alternatively, cells producing a hormone or growth-enhancing or -inhibitory factor might be in close association with target cells containing the receptor for such ligands, with the endocrine cell itself still not possessing such receptors. The demonstration by Todaro
Figure 16.12 Diagram of the formation and activation of latent complexes of TGF-β. Latent TGF-β consists of a noncovalent complex between the LAP form and the mature TGF-β. In the large latent com- plex, LAP is covalently bound to a protein called the latent TGF-β–binding protein (LTBP) by a disulfide linkage. These complexes may be either sequestered by extracellular matrix or activated by a cooperative proteolytic process involving the mannose-6-phosphate receptor and a surface-bound protease after secre- tion from the cell. Only the mature, biologically active, C-terminal domain of TGF-β binds to its signaling receptors. (Adapted from Roberts and Sporn, 1996, with permission of the authors and publisher.)
and his associates of the production of a transforming growth factor, TGF-α, soon led to the demonstration that cells producing this factor also possess the EGF receptor, thus allowing both the production and the stimulation by the growth factor product all within a single cell. This was termed autocrine secretion, and these three types of secretion are diagrammed in Figure 16.14. At first, this phenomenon was felt to be unique to neoplastic cells and to possibly explain their enormous growth advantage over their normal counterparts (cf. Todaro et al., 1981). During the past two decades, however, examples of both paracrine and autocrine secretion in normal cells have been reported (cf. Wysolmerski and Stewart, 1998; Tsao et al., 1993).
Figure 16.13 Diagram of the TGF-β heterotetramer receptor and its signaling pathway. Upon activation of the serine/threonine receptor kinase by interaction with its ligand, pathway-specific Smads are phospho- rylated leading to heterodimerization with Smad4, the complex then translocating to the nucleus where it binds directly, or in a complex with other factors, to DNA. The inhibitory Smads (Smad7) bind to the type
1 receptor and prevent phosphorylation of the pathway-specific Smads. (Adapted from Visser and Them- men, 1998, with permission of the authors and publisher.)