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Frontiers in Biology

Front Biol    2012, Vol. 7 Issue (1) : 1-13     https://doi.org/10.1007/s11515-011-1181-z
REVIEW
Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer
Peter E. ZAGE1,2,3(), Andrew J. BEAN4,5
1. Department of Pediatrics, Section of Hematology-Oncology, 1102 Bates, Suite 1220, Houston, TX 77030, USA; 2. Texas Children's Cancer and Hematology Centers, Houston, TX 77030, USA; 3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA; 4. Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; 5. Division of Pediatrics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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Abstract

Growth factor receptors (GFRs) are often aberrantly expressed in tumor cells, and altered GFR expression and activity contribute to the pathogenesis of many types of cancer. A variety of mechanisms have been identified that result in enhanced GFR expression and activity in cancer cells. Defects in the pathways responsible for GFR internalization and intracellular trafficking are likely to be involved in altered GFR expression in a variety of cancers. The roles of GFR trafficking pathways in the regulation of GFR expression, in the pathogenesis of tumors, and in the response of tumors to treatment have not been fully delineated, but the likely contributions of GFR signaling to the development and progression of various malignancies suggest that therapies that modify GFR trafficking may be effective as anticancer treatments.

The intracellular trafficking of GFRs is regulated by a number of protein complexes and by protein ubiquitination. Many of the proteins required for this trafficking are products of tumor suppressor genes, and the expression and function of the protein machinery utilized for intracellular trafficking is frequently altered in tumor cells, consistent with the likely role of GFR trafficking in tumorigenesis. Many of the proteins involved in GFR trafficking have been identified as potential targets for anticancer treatment, and novel treatments directed against these targets are currently in preclinical development and in clinical trials. Ubiquitin ligases are critical for GFR trafficking and represent potentially important targets for the development of novel therapies.

The genes for the ubiquitin ligases c-Cbl and UBE4B are located in chromosome regions commonly altered in a variety of tumors and therefore are likely to be important for tumorigenesis. c-Cbl ubiquitinates a number of GFRs and directs them for degradation. Mutations in c-Cbl have been identified in cases of myeloid leukemia and myelodysplasia, providing a link between GFR ubiquitination and trafficking and leukemogenesis. We have shown that UBE4B plays a crucial role in GFR trafficking and degradation in tumor cells, suggesting a previously uncharacterized link between UBE4B and tumorigenesis. With the critical need for new and effective therapies for pediatric malignancies, the recently identified roles for the GFR trafficking pathway in the pathogenesis of various forms of cancer confirm the importance of the further development of novel therapies targeting this pathway in children with cancer.

Keywords growth factor receptor      tyrosine kinase      trafficking      UBE4B      neuroblastoma     
Corresponding Author(s): ZAGE Peter E.,Email:zage@bcm.tmc.edu   
Issue Date: 01 February 2012
 Cite this article:   
Peter E. ZAGE,Andrew J. BEAN. Growth factor receptor trafficking as a potential therapeutic target in pediatric cancer[J]. Front Biol, 2012, 7(1): 1-13.
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http://journal.hep.com.cn/fib/EN/Y2012/V7/I1/1
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Fig.1  Trafficking Pathways for Sorting, Recycling, and Degradation of Growth Factor Receptors (GFRs). Following internalization, GFR-containing vesicles fuse with the early endosome (A). From the early endosome, GFRs can be recycled back to the cell surface via recycling endosomes (B) and/or remain in the endosome as it matures into a multi-vesicular body (MVB) (C). GFRs may also be recycled back to the plasma membrane from the MVB (not shown). Remaining GFRs are then sorted into internal vesicles of the MVB in an ESCRT-mediated, ubiquitin-dependent pathway. MVB fusion with lysosomes results in the degradation of MVB vesicles and their contents (D).
Protein Ubiquitination Pathway. The E1 activating enzyme activates ubiquitin using one molecule of ATP (1). Activated ubiquitin is then transferred to the E2 ubiquitin conjugating enzyme (2). E3 ubiquitin protein ligases transfer the ubiquitin molecules from the E2 enzyme to substrates at the early endosome for lysosomal targeting or in the cytosol for proteasomal degradation, after additional polyubiquitination by E4 ligases (3). Deubiquitination of endosomal substrates occurs after ESCRT-mediated sorting but before MVB lumenal vesicle formation, while deubiquitination of cytosolic substrates occurs during proteasomal degradation (4), allowing for the maintenance of a constant pool of cytoplasmic ubiquitin.
Fig.2  UBE4B mediates EGFR degradation. (A) HeLa and SKNAS neuroblastoma cells were starved, then stimulated with EGF for 0, 30, or 60 minutes. Cell lysates were then examined by immunoblotting for EGFR content. SKNAS cells (red bars) have greater amounts of remaining EGFR, suggesting slower degradation rates, than HeLa cells (blue bars). (B) Cell lysates of untransfected HeLa cells or HeLa cells transfected with shRNA (RNAI)to UBE4B were probed with antibodies to EGFR to show decreased rates of EGFR degradation with UBE4B depletion. Control HeLa cells were transfected with empty vector or with a scrambled shRNA sequence. The results are presented as the amount of remaining EGFR at 45 minutes vs. the amount of EGFR present at 0 minutes (*denotes <0.05).
Fig.3  Outcomes of neuroblastoma patients based on expression. The NCI Oncogenomics databases were evaluated for outcomes of neuroblastoma patients (http://pob.abcc.ncifcrf.gov/cgi-bin/JK). The resulting Kaplan-Meier curve shows overall survival of patients with low (blue) and high (red) gene expression (<0.001).
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