PTK Subfamilies

In the human genome, 58 genes encode PTK receptors [2,36]. Each receptor consists of an extracellular ligand-binding part, a single transmembrane domain, and an intra-cellular part with an intrinsic kinase domain. Based on their overall structures, the PTK receptors can be placed into 20 subfamilies (Fig. 1). Individual subfamilies are characterized by specific structural motifs in their extracellular parts (e.g., Ig-like domains and fibronectin type III domains). Moreover, the sequences of the kinase domains are normally more similar within the subfamilies than between the subfamilies. The major families are briefly introduced below (for reviews, see Fantl et al. [8] and Schlessinger [29]).

The epidermal growth factor (EGF) receptor was the first PTK receptor to be identified. The four members of the family are important for the morphogenesis of epithelial tissues. Members of this family are often amplified or activated through mutations in human malignancies.

The three members of the insulin receptor family are disulfide-bonded dimers that undergo cleavage during processing to generate a- and P-subunits. In addition to the well-known metabolic effects mediated by the insulin receptor, this family mediates important survival signals.

The platelet-derived growth factor (PDGF) family members are characterized by 5 Ig-like domains in the extracellular domain and by the presence of an intervening sequence that splits the kinase into two parts. PDGF receptors are of particular importance for the development of the connective tissue compartments of various organs, as well as for the development of smooth muscle cells of blood vessels. The related receptors for stem cell factor and colony-stimulating factor 1 (CSF-1) are implicated, for example, in the development of hematopoietic cells, germ and neuronal cells, and macrophages.

The vascular endothelial cell growth factor (VEGF) receptor family members have seven Ig-like domains extracellu-larly and are primarily expressed on endothelial cells; thus, they are implicated in vasculogenesis, angiogenesis, and lymphangiogenesis.

The fibroblast growth factor (FGF) receptor family members are characterized by three Ig-like domains extracellu-larly, although splice variants with only two Ig-like domains have been described. Like the VEGF receptors, FGF receptors are expressed on endothelial cells and are implicated in angiogenesis; however, these receptors are also expressed in other cell types and have important roles in the embryonal development of several organs and tissues.

Figure 1 Organization of human PTK receptors in 20 subfamilies of structurally related receptors. The designations of the members in each family are given below each schematic figure. Receptors implicated in malignancies are written in italics and bold. An asterisk after the name indicates that the PTK receptor has an inactive kinase domain. (From Blume-Jensen, P. and Hunter, T., Nature, 411, 355-365, 2001. With permission.)

Figure 1 Organization of human PTK receptors in 20 subfamilies of structurally related receptors. The designations of the members in each family are given below each schematic figure. Receptors implicated in malignancies are written in italics and bold. An asterisk after the name indicates that the PTK receptor has an inactive kinase domain. (From Blume-Jensen, P. and Hunter, T., Nature, 411, 355-365, 2001. With permission.)

Members of the neurotrophin receptor family (TrkA, B, and C) bind members of the NGF family of neurotrophins and have important functions during the development and maintenance of the central nervous system.

The two members of the hepatocyte growth factor (HGF) receptor family (Met and Ros) undergo cleavage of their extracellular domains after their syntheses. They have important roles in regulation of cell motility and in organ morphogenesis during embryonal development.

The Eph receptor family, the largest of the PTK receptor subfamilies, has 14 members. Eph receptors are expressed in the nervous system and also in endothelial cells; thus, they are implicated in neuronal guidance and angiogenesis. Interestingly, one class of their ligands, ephrin-Bs, are also transmembrane molecules expressed on the surface of cells; binding of ephrin-Bs to Eph receptors leads not only to activation of the Eph PTK receptor but also to initiation of signaling events at the intracellular part of the ephrin molecules [31].

The remaining PTK subfamilies generally consist of single members and are generally less well characterized. Interestingly, one of these families, the DDR family, has collagens as ligands [33,38], thus exemplifying the observation that PTK receptors mediate signals not only from soluble or membrane-associated growth factors but also from the surrounding extracellular matrix.

Of note is that three examples of PTK receptor family members have mutations in their kinase domains, rendering them devoid of kinase activity (Fig. 1); however, they may still have important roles in signaling (see later discussion).

In general, each subfamily binds a family of structurally related ligands. The specificity is not always absolute within the subfamilies; several receptors bind more than one ligand and several ligands bind more than one receptor. In contrast, high-affinity interactions of individual ligands with more than one subfamily of PTK receptors, or of individual PTK receptors with more than one class of ligands, have not been observed.

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