{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T03:32:23Z","timestamp":1776310343544,"version":"3.50.1"},"reference-count":59,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2003,4,24]],"date-time":"2003-04-24T00:00:00Z","timestamp":1051142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Developmental Dynamics"],"published-print":{"date-parts":[[2003,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Branching morphogenesis of fetal mouse submandibular glands (SMGs) partly depends on the epidermal growth factor (EGF) receptor that triggers at least three intracellular signaling pathways involving (1) the mitogen\u2010activated protein kinases ERK\u20101\/2, (2) phospholipase C\u03b31 (PLC\u03b31), and (3) phosphatidylinositol\u20103\u2010kinase (PI3K). PLC\u03b31 directly activates protein kinase C (PKC) isozymes; PI3K stimulates protein kinase B (PKB, also known as Akt), which ultimately activates PKCs and other proteins. We reported that the pattern of phosphorylation of ERK\u20101\/2 in response to EGF in SMGs varies with fetal age and that blockade of EGF\u2010stimulated ERK\u20101\/2 signaling partially inhibits branching (Kashimata et al. [2000] Dev. Biol. 220:183\u2013196). Here, we report on components of the PLC\u03b31, PI3K, and PKC families of signaling molecules in fetal SMGs from the 13th day of gestation to postnatal ages. Western blotting revealed that (1) PLC\u03b31 is present from E13 to E18 but drops off precipitously to negligible levels on the day of birth and thereafter, and (2) PI3K, PKB(Akt), and several PKC isozymes are expressed from E13 onward through adult life. Both PLC\u03b31 and PI3K are phosphorylated in response to EGF. Inhibition of PI3K by LY294002 inhibited EGF\u2010stimulated branching, but inhibition of PLC\u03b31 by U73122 had no effect. Western blotting showed that the concentrations of 8 PKC isozymes vary with age in the fetal and postnatal SMG. However, general inhibition of PKCs by Calphostin C or specific inhibition of PKC\u03b1 or of PKC\u03f5 by G\u00f66976 or Ro\u201032\u20100432, respectively, increased EGF\u2010stimulated branching. Calphostin C also increased EGF\u2010stimulated phosphorylation of ERK\u20101\/2. These findings indicate that signaling from the EGF receptor in the fetal mouse SMG varies with development and triggers stimulatory effects by means of ERK\u20101\/2 and PI3K but inhibitory effects by means of PKC isozymes. Developmental Dynamics 227:216\u2013226, 2003. \u00a9 2003 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/dvdy.10309","type":"journal-article","created":{"date-parts":[[2003,5,19]],"date-time":"2003-05-19T07:34:22Z","timestamp":1053329662000},"page":"216-226","source":"Crossref","is-referenced-by-count":44,"title":["EGF\u2010stimulated signaling by means of PI3K, PLC\u03b31, and PKC isozymes regulates branching morphogenesis of the fetal mouse submandibular gland"],"prefix":"10.1002","volume":"227","author":[{"given":"Noriko","family":"Koyama","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masanori","family":"Kashimata","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Sakashita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Sakagami","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward 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