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FGF-induced phospholipase Cγ signaling regulates lacrimal gland branching by competing with PI3K in phosphoinositide metabolism

Published:26 August 2025 DOI: 10.1016/j.celrep.2025.116046 PMID: 40711883
Qian Wang,?Chenqi Tao,?Yihua Wu,?Karen E Anderson,?Neoklis Makrides,?Abdul Hannan,?John Peregrin,?Chyuan-Sheng Lin,?Zhipeng Ding,?Wei Li,?Phillip Hawkins,?Len Stephens,?Xin Zhang

Abstract

Although the regulation of branching morphogenesis by spatially distributed cues is well established, the underlying intracellular signaling mechanisms are not well understood. The development of the lacrimal gland is driven by fibroblast growth factor (FGF) signaling, which activates phospholipase C gamma (PLCγ). Here, we showed that mutating the PLCγ1 binding site on Fgfr2 leads to ectopic branching and hyperplasia in the lacrimal gland, which was phenocopied by either deleting PLCγ1 or disabling any of its SH2 domains. PLCγ1 inactivation did not change the level of Fgfr2 or affect mitogen-activated protein kinase (MAPK) signaling but instead led to sustained AKT phosphorylation due to increased phosphatidylinositol 3,4,5-trisphosphate (PIP3) production. Consistent with this, the PLCγ1 mutant phenotype can be reproduced by the elevation of phosphatidylinositol 3-kinase (PI3K) signaling in Pten knockout and attenuated by blocking AKT signaling. Our findings demonstrate that FGF-activated PLCγ modulates PI3K signaling by shifting phosphoinositide metabolism, revealing the crucial role of PLCγ in branching morphogenesis and organ size control.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione 425637-18-9 C25H22N6O2 156 suppliers $10.00-$2839.00
3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione 425637-18-9 C25H22N6O2 156 suppliers $10.00-$2839.00
3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione 425637-18-9 C25H22N6O2 156 suppliers $10.00-$2839.00
3-(1H-Indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione 425637-18-9 C25H22N6O2 156 suppliers $10.00-$2839.00
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