The adhesion GPCR latrophilin – a novel signaling cascade in oriented cell division and anterior-posterior polarity

Abstract

Although several signaling pathways in oriented cell division have been well characterized such as delta/notch inductions or wnt/frizzled-based anterior-posterior polarity, there is strong evidence for additional signal pathways controlling early anterior-posterior polarity decisions. The homolog of the adhesion G protein-coupled receptor latrophilin, LAT-1 has been identified as a receptor essential for oriented cell division in an anterior-posterior direction of specific blastomeres in the early C. elegans embryo. We recently conducted a study aiming at clarifying the signals involved in LAT-1 function. We identified a G s protein/adenylyl cyclase/cAMP pathway in vitro and demonstrated its physiological relevance in oriented cell division. By interaction with a G s protein LAT-1 elevates cAMP levels. These data indicate that G-protein signaling in oriented cell division is not solely GPCR-independent. This commentary will discuss our findings in the context of the current knowledge of mechanisms controlling oriented cell division and anterior-posterior polarity. Further, we identify open questions which need to be addressed in the future.

Structural Basis for Teneurin Function in Circuit-Wiring: A Toxin Motif at the Synapse

“…Although TENs and LPHNs are co-expressed and have key roles during embryogenesis, the role of the TEN/LPHN interaction in embryonic development has not been studied. LPHNs were reported to mediate embryogenesis in C. elegans by modulating intracellular cAMP levels (Winkler and Promel, 2016), prompting us to test whether human TEN binding to LPHN also induces trans-cellular cAMP signaling. We established a cAMP-based signaling assay for LPHN1 or LPHN-3 in mammalian cells (Figure 4D–E and Figure S7A–F), and used it as a readout to monitor receptor activity.…”

“…Similar to TENs, LPHNs are also conserved between vertebrates and invertebrates, have broad expression patterns, and are involved in embryogenesis (Langenhan et al, 2009; Muller et al, 2015; Scholz et al, 2015). In both C. elegans and Drosophila , LPHN was suggested to act in development by modulating cAMP levels (Scholz et al, 2017; Winkler and Promel, 2016). Considering that cAMP regulates diverse cellular functions including migration, adhesion and differentiation, our results suggest a role for the TEN-LPHN interaction and the subsequent modulation of cAMP levels in various contexts, including development.…”

Catching Latrophilin With Lasso: A Universal Mechanism for Axonal Attraction and Synapse Formation

“…Thus, exogenous Stachel peptide caused a pertussis toxin-sensitive decrease in cAMP levels (Nazarko et al, 2018). By contrast, NTF ligands usually increase cAMP levels (Figure 1C, left) [e.g., after activation of LAT-1 by its endogenous ligand in Caenorhabditis elegans (Winkler and Prömel, 2016) or activation of rat LPHN1 expressed in COS7 cells by LTX (Lelianova et al, 1997)]. Also, the NTF-CTF complex did not bind Gαi in pull-down experiments (while Gαs was not tested) (Rahman et al, 1999).…”