scholarly journals NELL2-mediated lumicrine signaling through OVCH2 is required for male fertility

Science ◽  
2020 ◽  
Vol 368 (6495) ◽  
pp. 1132-1135 ◽  
Author(s):  
Daiji Kiyozumi ◽  
Taichi Noda ◽  
Ryo Yamaguchi ◽  
Tomohiro Tobita ◽  
Takafumi Matsumura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Male Fertility ◽  
Reproductive Tract ◽  
Surface Protein ◽  
Orphan Receptor ◽  
Testicular Germ Cell ◽  
Male Reproductive Tract ◽  
Kinase C ◽  
Epidermal Growth

The lumicrine system is a postulated signaling system in which testis-derived (upstream) secreted factors enter the male reproductive tract to regulate epididymal (downstream) pathways required for sperm maturation. Until now, no lumicrine factors have been identified. We demonstrate that a testicular germ-cell–secreted epidermal growth factor–like protein, neural epidermal growth factor–like–like 2 (NELL2), specifically binds to an orphan receptor tyrosine kinase, c-ros oncogene 1 (ROS1), and mediates the differentiation of the initial segment (IS) of the caput epididymis. Male mice in which Nell2 had been knocked out were infertile. The IS-specific secreted proteases, ovochymase 2 (OVCH2) and A disintegrin and metallopeptidase 28 (ADAM28), were expressed upon IS maturation, and OVCH2 was required for processing of the sperm surface protein ADAM3, which is required for sperm fertilizing ability. This work identifies a lumicrine system essential for testis-epididymis-spermatozoa (NELL2-ROS1-OVCH2-ADAM3) signaling and male fertility.

Mechanism of sodium transport inhibition by epidermal growth factor in cortical collecting ducts

1991 ◽  
Vol 261 (5) ◽  
pp. F896-F903 ◽  
Author(s):  
V. M. Vehaskari ◽  
J. Herndon ◽  
L. L. Hamm
Keyword(s):  
Signal Transduction ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Na Transport ◽  
Kinase C ◽  
Transport Inhibition ◽  
Collecting Ducts ◽  
Epidermal Growth

Epidermal growth factor (EGF) inhibits Na transport in the cortical collecting ducts (CCD). To gain insight into the signal transduction of this effect, several potential mechanisms were examined in rabbit CCD perfused in vitro. Pretreatment with pertussis toxin, indomethacin, or the protein kinase C inhibitor H7 did not prevent the acute 34-50% decrease in lumen-to-bath 22Na flux (JNa) on exposure to peritubular EGF, indicating that the inhibition is not mediated by a Gi protein, prostaglandin E2 (PGE2), or protein kinase C. Inhibition of the basolateral Na-H exchanger was also without an effect. Lowering the bath Ca concentration from 1.2 to 0.11 mM did not prevent the inhibition of JNa by EGF (JNa decreased significantly by 38.7 +/- 6.9% and 29.1 +/- 5.3%, respectively); in contrast, reduction of the bath free Ca to 0.005 mM totally abolished the effect of EGF. The response to EGF was also assessed in the setting of chronic stimulation of Na transport; inhibition of JNa by EGF was still observed in CCD from remnant kidneys and in CCD from mineralocorticoid-treated rabbits. The results demonstrate that the inhibition of CCD Na transport by EGF is dependent on peritubular Ca. This suggests that the signal transduction involves Ca influx across the basolateral membrane and that increased cytosolic free Ca may be a common pathway for the counterregulatory control of Na reabsorption by several agonists.

scholarly journals Regulation of epidermal-growth-factor-receptor signal transduction by cis-unsaturated fatty acids. Evidence for a protein kinase C-independent mechanism

1991 ◽  
Vol 278 (3) ◽  
pp. 679-687 ◽  
Author(s):  
X Casabiell ◽  
A Pandiella ◽  
F F Casanueva
Keyword(s):  
Signal Transduction ◽  
Fatty Acids ◽  
Protein Kinase C ◽  
Oleic Acid ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Cell Lines ◽  
Kinase C ◽  
Epidermal Growth

The effect of acute treatment with non-esterified fatty acids (NEFA) on transmembrane signalling has been investigated in three different cell lines. In EGFR T17 cells, pretreatment with cis-unsaturated (oleic and palmitoleic acids) NEFA, but not with saturated or trans-unsaturated NEFA, inhibited the epidermal-growth-factor (EGF)-induced increases in cytosolic [Ca2+], membrane potential and Ins(1,4,5)P3 generation. The blocking effect was found to be time- and dose-dependent and rapidly reversible after washout. However, oleic acid treatment did not block either binding of 125I-EGF to its receptor or EGF-induced autophosphorylation of the EGF receptor. The mechanism of action of NEFA could not be attributed to protein kinase C activation, since (i) down-regulation of the enzyme by long-term treatment with phorbol esters did not prevent blockade by oleic acid, and (ii) the effects of acutely administered phorbol ester and oleic acid were additive. In this cell line, signalling at bradykinin and bombesin receptors was also impaired by oleic acid. In A431 cells, oleic acid also blocked signal transduction at the EGF and B2 bradykinin receptors. Finally, in PC12 cells, oleic acid blocked the Ca2+ influx mediated by the activation of B2 bradykinin receptors. In conclusion: (1) NEFA block signal transduction by interfering with receptor-phospholipase C or phospholipase C-substrate interaction without preventing ligand binding; (2) NEFA do not act by a protein kinase C-mediated mechanism; (3) the effect of NEFA is dependent on their configuration rather than hydrophobicity or chain length; (4) this effect is evident in several different cell lines and receptor systems.

scholarly journals Induction of heparin-binding epidermal growth factor-like growth factor mRNA by protein kinase C activators

1994 ◽  
Vol 46 (3) ◽  
pp. 690-695 ◽  
Author(s):  
Mian-Shin Tan ◽  
Jer-Chia Tsai ◽  
Yau-Jiunn Lee ◽  
Hung-Chun Chen ◽  
Shyi-Jang Shin ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Heparin Binding ◽  
Kinase C ◽  
Protein Kinase C Activators ◽  
Epidermal Growth

scholarly journals Epidermal Growth Factor Activates Phosphoinositide Turnover and Protein Kinase C in BALB/MK Keratinocytes

1988 ◽  
Vol 2 (9) ◽  
pp. 799-805 ◽  
Author(s):  
Jorge Moscat ◽  
Christopher J. Molloy ◽  
Timothy P. Fleming ◽  
Stuart A. Aaronson
Keyword(s):  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Epidermal Growth Factor ◽  
Phosphoinositide Turnover ◽  
Kinase C ◽  
Epidermal Growth

scholarly journals A Common Cross-species Function for the Double Epidermal Growth Factor-like Modules of the Highly DivergentPlasmodiumSurface Proteins MSP-1 and MSP-8

2004 ◽  
Vol 279 (19) ◽  
pp. 20147-20153 ◽  
Author(s):  
Damien R. Drew ◽  
Rebecca A. O'Donnell ◽  
Brian J. Smith ◽  
Brendan S. Crabb
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Drug Targets ◽  
Point Mutations ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Surface Proteins ◽  
Parasite Line ◽  
Asexual Blood Stage ◽  
Epidermal Growth

An understanding of structural and functional constraints on the C-terminal double epidermal growth factor (EGF)-like modules of merozoite surface protein (MSP)-1 and related proteins is of importance to the development of these molecules as malaria vaccines and drug targets. Using allelic replacement, we show thatPlasmodium falciparumparasites can invade erythrocytes and grow efficiently in the absence of an MSP-1 protein with authentic MSP-1 EGF domains. In this mutant parasite line, the MSP-1 EGFs were replaced by the corresponding double EGF module fromP. bergheiMSP-8, the sequence of which shares only low identity with its MSP-1 counterpart. Hence, the C-terminal EGF domains of at least somePlasmodiumsurface proteins appear to perform the same function in asexual blood-stage development. Mapping the surface location of the few residues that are common to these functionally complementary EGF modules revealed the presence of a highly conserved pocket of potential functional significance. In contrast to MSP-8, an even more divergent double EGF module, that from the sexual stage protein PbS25, was not capable of complementing MSP-1 EGF function. More surprisingly, two chimeric double EGF modules comprising hybrids of the EGF domains fromP. falciparumandP. chabaudiMSP-1 were also not capable of replacing theP. falciparumMSP-1 EGF module. Together, these data suggest that although the MSP-1 EGFs can accommodate extensive sequence diversity, there appear to be constraints that may restrict the simple accumulation of point mutations in the face of immune pressure in the field.

Epidermal growth factor binding and receptor distribution in the mouse reproductive tract during development

1990 ◽  
Vol 142 (1) ◽  
pp. 75-85 ◽  
Author(s):  
Nancy L. Bossert ◽  
Karen G. Nelson ◽  
Kimberly A. Ross ◽  
Tsuneo Takahashi ◽  
John A. McLachlan
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Reproductive Tract ◽  
Factor Binding ◽  
Epidermal Growth ◽  
Receptor Distribution
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