Adp

Ligand-independent receptor oncoproteins

▲ FIGURE 23-14 Effects of oncogenic mutations in proto-oncogenes that encode cell-surface receptors. Left: A mutation that alters a single amino acid (valine to glutamine) in the transmembrane region of the Her2 receptor causes dimerization of the receptor, even in the absence of the normal EGF-related ligand, making the oncoprotein Neu a constitutively active kinase. Right: A deletion that causes loss of the extracellular ligand-binding domain in the EGF receptor leads, for unknown reasons, to constitutive activation of the kinase activity of the resulting oncoprotein ErbB.

from a point mutation in the extracellular domain. In other cases, deletion of much of the extracellular ligand-binding domain produces a constitutively active oncogenic receptor. For example, deletion of the extracellular domain of the normal EGF receptor converts it to the dimeric ErbB oncopro-tein (Figure 23-14, right).

Mutations leading to overproduction of a normal RTK also can be oncogenic. For instance, many human breast cancers overproduce a normal Her2 receptor. As a result, the cells are stimulated to proliferate in the presence of very low concentrations of EGF and related hormones, concentrations too low to stimulate proliferation of normal cells.

0A monoclonal antibody specific for Her2 has been a strikingly successful new treatment for the subset of breast cancers that overproduce Her2. Her2 antibody injected into the blood recognizes Her2 and causes it to be internalized, selectively killing the cancer cells without any apparent effect on normal breast (and other) cells that produce moderate amounts of Her2. I

Another mechanism for generating an oncogenic receptor is illustrated by the human trk oncogene, which was isolated from a colon carcinoma. This oncogene encodes a chimeric protein as the result of a chromosomal translocation that replaced the sequences encoding most of the extracellular domain of the normal Trk receptor with the sequences encoding the N-terminal amino acids of nonmuscle tropo-myosin (Figure 23-15). The translocated tropomyosin segment can mediate dimerization of the chimeric Trk receptor by forming a coiled-coil structure, leading to activation of the kinase domains in the absence of ligand. The normal Trk protein is a cell-surface receptor tyrosine kinase that binds a nerve growth factor (Chapter 22). In contrast, the constitutively active Trk oncoprotein is localized in the cytosol, since the N-terminal signal sequence directing it to the membrane has been deleted.

Exterior

Cytosol

Exterior

Cytosol

Extracellular domain

Transmembrane domain

Kinase domain

Normal Trk receptor

Normal nonmuscle tropomyosin

Extracellular domain

Transmembrane domain

Kinase domain

Normal Trk receptor

Normal nonmuscle tropomyosin

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N-terminal region of tropomyosin

Chimeric Trk oncoprotein

► FIGURE 23-15 Domain structures of normal tropomyosin, the normal Trk receptor, and chimeric Trk oncoprotein.

A chromosomal translocation results In replacement of most of the extracellular domain of the normal human Trk protein, a receptor tyrosine kinase, with the N-terminal domain of nonmuscle tropomyosin. Dimerized by the tropomyosin segment, the Trk oncoprotein kinase is constitutively active. Unlike the normal Trk, which is localized to the plasma membrane, the Trk oncoprotein is found in the cytosol. [See F. Coulier et al., 1989, Mol. Cell Biol. 9:15.]

Viral Activators of Growth-Factor Receptors Act as Oncoproteins

Viruses use their own tricks to cause cancer, presumably to increase the production of virus from the infected cancer cells. For example, a retrovirus called spleen focus-forming virus (SFFV) induces erythroleukemia (a tumor of erythroid progenitors) in adult mice by manipulating a normal developmental signal. The proliferation, survival, and differentiation of erythroid progenitors into mature red cells absolutely require erythropoietin (Epo) and the corresponding Epo receptor (see Figure 14-7). A mutant SFFV envelope glycoprotein, termed gp55, is responsible for the oncogenic effect of the virus. Although gp55 cannot function as a normal retrovirus envelope protein in virus budding and infection, it has acquired the remarkable ability to bind to and activate Epo receptors in the same cell (Figure 23-16). By inappropriately and continuously stimulating the proliferation of erythroid progenitors, gp55 induces formation of excessive numbers of erythrocytes. Malignant clones of erythroid progenitors emerge several weeks after SFFV infection as a result of further mutations in these aberrantly proliferating cells.

Another example of this phenomenon is provided by human papillomavirus (HPV), a DNA virus that causes genital warts. A papillomavirus protein designated E5, which contains only 44 amino acids, spans the plasma membrane and forms a dimer or trimer. Each E5 polypeptide can form a

▲ FIGURE 23-16 Activation of the erythropoietin (Epo) receptor by the natural ligand, Epo, or a viral oncoprotein.

Binding of Epo dimerizes the receptor and induces formation of erythrocytes from erythroid progenitor cells. Normally cancers occur when progenitor cells infected by the spleen focus-forming virus produce the Epo receptor and viral gp55, both localized to the plasma membrane. The transmembrane domains of dimeric gp55 specifically bind the Epo receptor, dimerizing and activating the receptor in the absence of Epo. [See S. N. Constantinescu et al., 1999, EMBO J. 18:3334.]

stable complex with one endogenous receptor for PDGF, thereby aggregating two or more PDGF receptors within the plane of the plasma membrane. This mimics hormonemediated receptor dimerization, causing sustained receptor activation and eventually cell transformation.

Many Oncogenes Encode Constitutively Active Signal-Transduction Proteins

A large number of oncogenes are derived from proto-oncogenes whose encoded proteins aid in transducing signals from an activated receptor to a cellular target. We describe several examples of such oncogenes; each is expressed in many types of tumor cells.

Ras Pathway Components Among the best-studied onco-genes in this category are the rasD genes, which were the first nonviral oncogenes to be recognized. A point mutation that substitutes any amino acid for glycine at position 12 in the Ras sequence can convert the normal protein into a consti-tutively active oncoprotein. This simple mutation reduces the protein's GTPase activity, thus maintaining Ras in the active GTP-bound state. Constitutively active Ras oncoproteins are produced by many types of human tumors, including bladder, colon, mammary, skin, and lung carcinomas, neuroblastomas, and leukemias.

As we saw in Chapter 14, Ras is a key component in transducing signals from activated receptors to a cascade of protein kinases. In the first part of this pathway, a signal from an activated RTK is carried via two adapter proteins to Ras, converting it to the active GTP-bound form (see Figure 14-16). In the second part of the pathway, activated Ras transmits the signal via two intermediate protein ki-nases to MAP kinase. The activated MAP kinase then phos-phorylates a number of transcription factors that induce synthesis of important cell-cycle and differentiation-specific proteins (see Figure 14-21). Activating Ras mutations short-circuit the first part of this pathway, making upstream activation triggered by ligand binding to the receptor unnecessary.

Oncogenes encoding other altered components of the RTK-Ras-MAP kinase pathway also have been identified. One example, found in certain transforming mouse retro-viruses, encodes a constitutively activated Raf serine/threo-nine kinase, which is in the pathway between Ras and MAP kinase. Another is the crk (pronounced "crack") oncogene found in avian sarcoma virus, which causes certain tumors when overexpressed. The Crk protein, which contains one SH2 and two SH3 domains, is similar to the GRB2 adapter protein that functions between an RTK and Ras (see Figure 14-16). The SH2 and SH3 domains in GRB2 and other adapter proteins mediate formation of specific protein aggregates that normally serve as signaling units for cellular events. Overproduction of Crk leads to formation of protein aggregates that inappropriately transduce signals, thus

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