July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Role of ErbBs in PCO-related TGFβ signaling
Author Affiliations & Notes
  • Linda Musil
    Biochemistry & Molecular Biology, Oregon Health & Science Univ, Portland, Oregon, United States
  • Footnotes
    Commercial Relationships   Linda Musil, None
  • Footnotes
    Support  NIH Grant EY028558
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 6444. doi:
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      Linda Musil; Role of ErbBs in PCO-related TGFβ signaling. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6444.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose : EGFR1 (ErbB1) is a one of four members of the ErbB family. Each ErbB has distinct biological activities, due in part to the types of ligands they bind, their ability to recruit different signaling molecules, and their propensity to be endocytosed and/or degraded in response to ligand. Further functional diversity arises from the formation of ErbB heterodimers. Despite evidence from chick, rat, and human systems that ErbB inhibitors block key PCO-causing processes including myofibroblast differentiation, little is known about the expression of ErbBs and their ligands in the lens at the protein level. The goal of this study was to investigate ErbB signaling in lens cells and how the various family members interact with the TGFβ pathway as a first step towards understanding the mechanism by which ErbBs regulate PCO-causing processes.

Methods : Western blotting was used to assess expression of ErbB1, 2, and 4 in whole cell lysates, or on the plasma membrane following cell surface biotinylation, in serum-free primary chick lens cell cultures (DCDMLs). Secretion of bioactive ErbB ligands was assessed by examining the ability of DCDML conditioned medium to stimulate the activation (tyrosine autophosphorylation) of ErbBs in HEK cell recipients. Activation of ErbBs, ERK, and AKT was assessed using phospho-specific antibodies. Among the inhibitors used was lapatinib, a well-tolerated and very selective ErbB kinase blocker in current clinical use for breast cancer.

Results : Lens epithelial cell cultures express ErbB 1, 2, and 4 on the cell surface. Activation of ErbBs and ErbB-dependent ERK signaling is detectable in the absence of added ErbB ligand or TGFβ. Culturing cells with TGFβ does not induce detectable rapid transactivation of ErbBs, but modestly increases the level of bioactive ErbB ligand recoverable in cell conditioned medium after 48 h. TGFβ reduces the total and cell surface levels of ErbB2 and ErbB4, but increases the expression of ErbB1. Inhibition of ErbBs does not block growth factor-induced lens fiber cell differentiation.

Conclusions : Basal levels of ErbB activity appear to be sufficient for TGFβ to induce the level of pERK required to initiate myofibroblast differentiation. ErbB signaling also plays an important role in the later stages of TGFβ-induced myofibroblast formation, which is associated with an apparent switch from ErbB heterodimers to ErbB1 homodimers.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.


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