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Inside IOVS
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January 2002 |
Protein and Receptor Identification/Function in Ocular Tissues
IGF-1R Correlates in Uveal Melanoma
Uveal melanoma has a high mortality rate due to high incidence of metastases, which have a strong preference for the liver. Insulin-like growth factor-1 (IGF-1), produced mainly in the liver, binds to the IGF-1 receptor (IGF-1R). The expression of IGF-1R has been implicated in various human cancers. In this study All-Ericsson et al. (p. 1) demonstrate that IGF-1R is expressed in uveal melanoma and that a high expression is correlated with a poor clinical outcome. Furthermore, they conclude that uveal melanoma cell lines are strongly dependent on IGF-1R for growth and survival. These results raise the possibility of targeting IGF-1R for treatment of uveal melanoma.
Calcineurin in the Eye
Calcineurin (CaN) is a widely expressed Ca2+ and calmodulin stimulated protein-phosphatase, which provides a crucial link between intracellular Ca2+ and the phosphorylation state of various protein substrates. CaN is also the selective target of inhibition by the immunosuppressants cyclosporin and FK506. However, the distribution of CaN within the visual axis was unknown. Seitz et al. (p. 15) demonstrate that CaN is found to be present in all ocular tissues with largest expression in the cornea, retina and optic nerve. The authors propose that CaN may be involved in immunoregulation of the cornea, in modulation of photoreceptor transduction events, and in certain pathological conditions of the eye. Further studies utilizing CaN inhibitors in the future may reveal the full contribution which CaN has in ocular physiology.
The RP1 Protein is in the Photoreceptor Connecting Cilium
Mutations in the RP1 gene are the second most common cause of dominant retinitis pigmentosa, yet little is known about the RP1 protein. The data in this paper by Liu et al. (p. 22) show that the RP1 protein is specifically located in the connecting cilia of rod and cone photoreceptor cells. RP1 may thus be involved in the movement of proteins from the inner segment, through the connecting cilium, to their site of function in the outer segment. Investigation can now focus on determining if RP1 plays an active role in protein transport, or is a structural component of the ciliary axoneme, and how mutations in RP1 lead to photoreceptor cell death.
TGFb and PDGF Receptor in Fibroblast Contraction
Growth factors such as transforming growth factor (TGFb) and platelet-derived growth factor (PDGF) contribute to many fibrotic diseases. Here, Ikuno and Kazlauskas (p. 41) investigate the relationship between TGFb 1 and PDGF at the level of cellular contraction. They report that vitreous isolated from normal rabbits promotes contraction of fibroblasts, that TGFb is the major factor responsible, and that at least a portion of the TGFb-dependent contraction proceeds through the PDGF a receptor (aPDGFR), i.e. indirectly. Hence the aPDGFR is responsible for mediating cellular contraction of multiple growth factors: TGFb and members of the PDGF family.
CC-Chemokine Receptor 3 and Corneal Ulcer
Eosinophils in tears play a key role in the pathogenesis of allergy-related corneal ulcers. In the study by Fukagawa et al. (p. 58), tear samples from severe ocular allergic patients with corneal ulcer induced eosinophil chemotaxis comparable to 10 to 50 ng/ml of rh-eotaxin. This chemotaxis was reduced effectively by anti-CCR3 Ab. Inhibition of CCR3 on the eosinophil surface may represent a treatment strategy for severe allergy-related corneal ulcer.
Activin A and BMP-7 in Corneal Transdifferentiation
Growth factors belonging to the TGF-b superfamily play an important role in regulating myofibroblast transdifferentiation in corneal fibroblasts. You and Kruse (p. 72) show that the cornea transcribes activin A and corresponding receptors. Activin A and BMP-7 have different effects on the expression of myo-specific proteins and activation of the Smad signaling pathway. The authors report that blocking Smad signal transduction by antisense Smad 2/3 transfection or antagonizing activin-receptor binding by follistatin inhibits myofibroblast transdifferentiation.
CD44 in Glaucoma
The cell biology of POAG is characterized in part by the loss of TM and retinal ganglion cells. Knepper et al. (p. 133) have demonstrated that soluble CD44, the shed ectodomain of transmembrane CD44, is increased in POAG aqueous humor. Normally transmembrane CD44 is implicated in cell adhesion and in the presentation of growth factors to high affinity receptors. CD44 is required for erbB2-erbB3, receptor tyrosine kinases, which heterodimerize and promote cell survival. Soluble CD44 may compete with transmembrane CD44 for erbB2-erbB3 and, thereby, adversely influence the cell survival of TM and retinal ganglion cells in POAG.
TIGR/MYOC Localization and Interactions
Trabecular meshwork glucocorticoid inducible/myocilin (TIGR/MYOC) protein is linked to a subset of juvenile and adult onset primary open angle glaucomas. The normal function and cellular localization of TIGR/MYOC is currently an active and controversial area of research. Filla et al. (p. 151) show that TIGR/MYOC associates with the extracellular matrix (ECM) of human trabecular meshwork cultures treated with dexamethasone. TIGR/MYOC co-localizes with several ECM proteins including fibronectin, laminin and type IV collagen. Interactions between fibronectin and TIGR/MYOC involve the major heparin-binding domain of fibronectin. This finding provides an interesting lead to explore the role(s) of TIGR/MYOC in primary open angle glaucomas.
Myocilin Interactions
Myocilin gene mutations have been directly linked to approximately 3-4% of open angle glaucoma cases. The exact nature of myocilin and its function(s), however, remain unclear. Wentz-Hunter et al. (p. 176), through yeast two-hybrid analysis, confirmed the previous observation of myocilin/myocilin interactions to form homomultimers. They, in addition, discovered that myocilin interacts with a myosin regulatory light chain at both molecular and cellular levels. This finding provides an important link between myocilin and the actomyosin system that may be relevant to the function of myocilin in the trabecular meshwork and glaucoma.
IL-4 Receptors in Corneal Fibroblasts
Eotaxin released from interleukin-4(IL-4)–stimulated corneal fibroblasts is thought to contribute to the pathogenesis of corneal disorders associated with ocular allergic diseases. Corneal fibroblasts have now been shown in Fukuda et al. (p. 183) to express functional high-affinity IL-4 receptors (IL-4Rs) on their surface, and IL-4 was found to activate the transcriptional activator STAT6 in these cells. Eotaxin release from corneal fibroblasts stimulated by IL-4 and tumor necrosis factor–a was inhibited by neutralizing antibodies to the IL-4R. Inhibition of the IL-4R–STAT6 signaling pathway in corneal fibroblasts may thus represent a new approach to the treatment of corneal disorders associated with ocular allergic diseases.
Lens Proteomics
Rodents are useful experimental animals to test the significance of crystallin modifications in human lens. Ueda et al. (p. 205) and Lampi et al. (p. 216) examine the primary structures of rat and mouse crystallins and provide two-dimensional electrophoresis based maps of crystallins in these species. These maps will greatly speed the detection and assignment of post-translational modifications in experimental cataracts. Such information will help define modifications contributing to human cataract.
TNFa Regulation of MMPs during Neovascularization
It is postulated that hypoxia and growth factors are involved in the regulation of extracellular proteinase expression during retinal neovascularization. However, the factors and mechanisms which regulate the expression of the enzymes are not well characterized. The study by Majka et al. (p. 260) examines the potential role of tumor necrosis factor alpha (TNFa) as a regulator of matrix metalloproteinases (MMPs) in a murine model retinal neovascularization. TNFa levels increase in experimental mouse retinas exposed to hypoxic stimuli. The retinal microvascular endothelial cells are responsive to stimulation by TNFa which enhances the production of specific members of the MMP family. The vascular endothelial growth factor (VEGF) also plays a role in this process through its regulation of TNF alpha converting enzyme (TACE) and TNF receptor (p55) mRNA in the vascular endothelial cells.
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