PTK Receptors and Disease

Given the importance of PTK receptors in the control of cell proliferation and migration, it is not surprising that over-activity of PTK receptors occurs in cancer and other diseases that involve excess cell proliferation, such as inflammatory and fibrotic conditions and psoriasis. About half of the PTK receptors are implicated in various human malignancies (Fig. 1) [2]. Often, the receptors are constitutively activated by amplification or mutational events. Several mutations of PTK receptors cause constitutive dimerization (1) by mutations affecting disulfide bonding in the extracellular parts of the receptors, thus causing the formation of covalent dimers, mutations of other residues in the transmembrane, or jux-tamembrane domains that promote dimerization; or (2) by formation of fusion proteins between the kinase domains of the receptors and proteins that normally occur as dimers or oligomers. The end result is a constitutively active kinase that drives cell growth.

Another mechanism of activation of PTK receptors seen in disease is overproduction of the corresponding ligand. If a cell produces a growth factor for which it has the corresponding receptor, autocrine stimulation of growth may result. Alternatively, the growth factor may stimulate cells in the environment in a paracrine manner, which is relevant in tumor progression. Tumor-derived factors (e.g., VEGFs and FGFs) act on angiogenic PTK receptors and cause vascularization of the tumors, which is a prerequisite for tumor growth [9]. Likewise, other growth factors produced by tumor cells (e.g., PDGFs) may stimulate the formation of tumor stroma, which is important for the balanced growth of tumors [43].

Given the importance of PTK receptors for serious diseases, clinically useful PTK receptor antagonists are warranted. Several types of antagonists are currently used clinically or are in clinical trials for cancer, including a monoclonal-antibody-recognizing ErbB2 and low-molecular-weight selective inhibitors of various tyrosine kinases [12]. It is likely that PTK receptor antagonists will be important tools in the treatment of cancer and possibly other diseases characterized by an excessive cell growth.

Acknowledgments

Ingegard Schiller is thanked for her valuable help in the preparation of this manuscript. For space reasons, referencing has been kept to a minimum, and I apologize to authors who have not been properly referenced.

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