Andrea Morrione, PhD
Philadelphia, PA 19107
(215) 923-0249 fax
Research and Clinical Interests
Characterization of Insulin-like Growth Factor Receptor I (IGF-IR) and IR-A (insulin receptor isoform A) function in bladder cancer initiation and progression. Role of the growth factor progranulin (proepithelin) and its receptor in bladder cancer. Characterization of the role of adaptor protein Grb10 in the regulation of IGF-IR and IR-A ubiquitination, trafficking, and signaling.
The tyrosine kinase type 1 insulin-like growth factor receptor (IGF-IR) plays a significant role in a variety of cellular processes including mitogenesis, differentiation and increased cell motility. Aberrant IGF-IR signaling contributes toward tumor progression through its antiapoptotic action and the induction of prometastatic pathways. Targeted depletion of the IGF-IR reverses the transforming phenotype and sensitizes cells to anticancer treatments in several cancer cell models, suggesting that the IGF-IR plays a broad role in cancer. The adaptor protein Grb10 interacts with the IGF-IR in a ligand-dependent manner serving as an important regulator of IGF-IR signaling. Grb10 functions as an adaptor protein by binding the E3 ubiquitin ligase Nedd4 serving to bring the ligase into close proximity to the IGF-IR such that ubiquitination occurs upon ligand stimulation. The ubiquitinated IGF-IR is subsequently targeted for degradation, giving rise to long-term attenuation of signaling, a process known as down-regulation. However, the precise molecular details by which Grb10 and Nedd4 serve to contribute to down-regulation of the IGF-IR remain poorly understood. We have recently shown that Grb10/Nedd4complex mediates multiubiquitination (monoubiquitination at multiple sites) of the IGF-IR, which is required for receptor internalization in clathrin-dependent and independent pathways. We are now focusing on the identification of novel proteins involved in IGF-IR sorting/recycling.
Another project more recently started is aimed at the characterization of IGF-IR function in bladder cancer. we demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues compared to non-malignant controls. We have investigated the role of the IGF-IR in bladder cancer using urothelial carcinoma-derived 5637 and T24 cells. Although activation of the IGF-IR did not appreciably affect their growth, it did promote migration and stimulate in vitro wound closure and invasion. These effects required the activation of the Akt and MAPK pathways and IGF-I induced Akt- and MAPK-dependent phosphorylation of paxillin, which relocated at dynamic focal adhesions and it was necessary for promoting motility in bladder cancer cells.
Our results support the hypothesis that the IGF-IR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia. The IGF-IR may also serve as a novel biomarker for bladder cancer.
Proepithelin is a secreted pluripotent growth factor that plays a significant role in cell proliferation and cell cycle progression in many cellular systems. Proepithelin is highly expressed in several aggressive tumors, where the malignancy grade correlates with its expression levels. Proepithelin is also promoting cell migration, and it is important in wound healing and tissue repair. Given its critical role in wound repair and cancer progression, proepithelin may prove a useful clinical target for prognosis and therapy. Despite the strong connections with growth control and cancer, proepithelins mode of action is not well understood. Furthermore, the proepithelin receptor and/or proteins that mediate the early stages of proepitelin signaling from the plasma membrane have not been identified.
<br>We are now investigating the role of proepithelin and novel proepithelin-binding trans-membrane proteins, which we hypothesize are either the proepithelin receptor or proteins involved in proepithelin signaling, in proliferation, migration and transformation of bladder and prostate cancer cells.
Most Recent Peer-Reviewed Publications
- The perlecan-interacting growth factor progranulin regulates ubiquitination, sorting, and lysosomal degradation of sortilin
- Insulin receptor isoforms in physiology and disease: An updated view
- Discoidin domain receptor 1 modulates insulin receptor signaling and biological responses in breast cancer cells
- Mechanisms of progranulin action and regulation in genitourinary cancers
- EphA2 is a functional receptor for the growth factor progranulin
- CD99 triggering induces methuosis of Ewing sarcoma cells through IGF-1R/RAS/Rac1 signaling
- Suppression of progranulin expression inhibits bladder cancer growth and sensitizes cancer cells to cisplatin
- IGF-I induces upregulation of DDR1 collagen receptor in breast cancer cells by suppressing MIR-199a-5p through the PI3K/AKT pathway
- Sortilin regulates progranulin action in castration-Resistant prostate cancer cells
- A novel role for drebrin in regulating progranulin bioactivity in bladder cancer
- Novel cross-talk between IGF-IR and DDR1 regulates IGF-IR trafficking, signaling and biological responses
- Metformin inhibits androgen-induced IGF-IR up-regulation in prostate cancer cells by disrupting membrane-initiated androgen signaling
- Ligand-mediated endocytosis and trafficking of the insulin-like growth factor receptor I and insulin receptor modulate receptor function
- Decorin differentially modulates the activity of insulin receptor isoform A ligands
- Growth of v-src-transformed cells in serum-free medium through the induction of growth factors
1integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1
- Dichotomy of decorin activity on the insulin-like growth factor-I system
- Proline-rich tyrosine kinase 2 (Pyk2) regulates IGF-I-induced cell motility and invasion of urothelial carcinoma cells
- Insulin and insulin-like growth factor II differentially regulate endocytic sorting and stability of insulin receptor isoform A
- Novel RasGRF1-derived Tat-fused peptides inhibiting Ras-dependent proliferation and migration in mouse and human cancer cells