Growth factors have become increasingly important in many different aspects of physiology. They are polypeptides and proteins that are conveniently divided into three groups. One group is made up of agents that foster the multiplication or development of various types of cells; NGF, insulin-like growth factor I (IGF-I), activins and inhibins, and epidermal growth factor (EGF) are examples. More than 20 have been described. The cytokines are a second group. These factors are produced by macrophages and lymphocytes, as well as other cells, and are important in regulation of the immune system (see Chapter 3). Again, more than 20 have been described. The third group is made up of the colony-stimulating factors that regulate proliferation and maturation of red and white blood cells.
Receptors for EGF, platelet-derived growth factor (PDGF), and many of the other factors that foster cell multiplication and growth have a single membrane-spanning domain with an intracellular tyrosine kinase domain (Figure 1). When ligand binds to a tyrosine kinase receptor, it first causes a dimerization of two similar receptors. The dimerization results in partial activation of the intracellular tyrosine kinase domains and a cross-phosphorylation to fully activate each other. One of the pathways activated by phosphorylation leads, through the small G-protein Ras, to MAP kinases, and eventually to the production of transcription factors in the nucleus that alter gene expression (Figure 2).
Fig1. Diagrammatic representation of guanylyl cyclases, tyrosine kinases, and tyrosine phosphatases. NT refers to the amino (NH2 ) terminus and CT to the carboxyl terminus of each protein. Individual molecules are as follows: ANP, atrial natriuretic peptide; GC, guanylyl cyclase domain; EGFR, epidermal growth factor receptor; PDGFR, platelet-derived growth factor receptor; PTK, protein tyrosine kinase domain (PTK is inactive in guanylyl cyclase); PTP, tyrosine phosphatase domain.
Fig2. One of the direct pathways by which growth factors alter gene activity. TKR, tyrosine kinase domain; Grb2, Ras activator/ controller; Sos, Ras activator; Ras, product of the ras gene; MAP K, mitogen-activated protein kinase; MAP KK, MAP kinase kinase; TF, transcription factors. There is a cross-talk between this pathway and the cAMP pathway, as well as a cross-talk with the IP3–DAG pathway.
Receptors for cytokines and colony-stimulating factors differ from the other growth factors in that most of them do not have tyrosine kinase domains in their cytoplasmic portions and some have little or no cytoplasmic tail. However, they initiate tyrosine kinase activity in the cytoplasm. In particular, they activate the so-called Janus tyrosine kinases (JAKs) in the cytoplasm (Figure 3). These in turn phosphorylate STAT proteins. The phosphorylated STATs form homo- and heterodimers and move to the nucleus, where they act as transcription factors. There are four known mammalian JAKs and seven known STATs. Interestingly, the JAK STAT pathway can also be activated by growth hormone and is another important direct path from the cell surface to the nucleus. However, it should be emphasized that both the Ras and the JAK–STAT pathways are complex and there is cross-talk between them and other signaling pathways dis cussed previously.
Fig3. Signal transduction via the JAK–STAT pathway. A) Inactive JAKs are associated with individual receptors. B) Ligand binding leads to dimerization of receptor and activation JAKs that phosphorylate tyrosine residues on opposing receptors and their associated JAK. C) STATs then associate with the phosphorylated receptors and JAKs in turn phosphorylate these STATs. D) Phosphorylated STATs dimerize and move to nucleus, where they bind to response elements on DNA.
Finally, note that the whole subject of second messengers and intracellular signaling has become immensely complex, with multiple pathways and interactions. It is only possible in a book such as this to list highlights and present general themes that will aid the reader in understanding the rest of physiology (Clinical Box 2–9).
