Question

During neuronal pathfinding, the growth cone of the neuron chemotaxes to the target cell in the brain it needs to reach. At that point, the growth cone touches the target cell and responds to it by creating an adhesions junction. What type of signaling activates chemotaxis? What type of signaling activates formation of the adhesions junction. Suggest a biochemical pathway that would activate and form the adhesions junction.

Answer 1

cAMP receptors and heterotrimeric G-proteins

The first step in chemotaxis involves recognition of cAMP by its seven transmembrane domain-containing receptors. Four such cAMP receptors (cAR1-4) have been identified in Dictyostelium. cAR1 exhibits high affinity for cAMP binding and is expressed during early development to mediate chemotactic aggregation of single amoeba. This function of cAR1 overlaps partially with that of cAR3, which also shows high affinity binding to cAMP. cAR2 and cAR4 are important for later developmental events, such as mound formation and culmination. cAR1 is coupled to heterotrimeric G-proteins, which consist of alpha, beta, and gamma subunits, and activates them upon association with cAMP. G-protein activation leads to local actin polymerization at the leading edge and drives pseudopod extension. How cAR1 activates heterotrimeric G-proteins remains to be determined; however, several models have been proposed. For example, one model hypothesizes that, prior to stimulation, G-proteins are associated with cAR1 and that cAMP binding releases the heterotrimeric G-proteins and activates them. Another model posits that G-proteins are transiently recruited to cAR1 upon cAMP binding and become activated.

Although cAR1 is uniformly distributed along the plasma membrane, interactions between cAMP and cAR1 are prolonged at the leading edge compared to the trailing edge during chemotaxis. These observations suggest that asymmetric activation might occur at the level of the receptor. However, this may not lead to robust amplification of downstream signaling as the extent of activation of the receptor-coupled G-protein shows only a modest bias toward the higher concentration of the gradient. Below, we summarize four major signaling pathways that are downstream of cAR1 and the G-proteins.

Four signaling pathways that control chemotaxis

1. Production and degradation of PtdInsP3 by PI3Ks and PTEN

2. PLA2: another lipid signaling pathway parallel to the PIP3 pathway

3. Soluble guanylyl cyclase: regulation at the leading and trailing edges

4. Ras GTPases and TorC2: crosstalk with the PIP3 pathway

Signaling from the Adherens Junction

To those new to the field of cell–cell adhesion, one only needs to watch a movie of a developing embryo or migrating monolayer of cells in culture to recognize the remarkably fluid yet coordinated nature of cell–cell adhesions. Indeed, observing such cell behaviors brings to mind two clear questions: How is cell–cell adhesion regulated and how is the state of cell contact communicated to the cell’s interior? A central role for the cadherin/catenin adhesive complex in these cell behaviors was initially inferred from early studies showing that embryonic tissues fail to undergo normal morphogenesis in the presence of antibodies to the extracellular domain of E-cadherin. This result implied that cells fail to send morphogenetic signals when cadherin function is perturbed. In this chapter, we focus on the nature of these signals, particularly those that impact gene expression. Other chapters in this volume address how cadherins signal more locally to alter the cortical actin cytoskeleton, which ultimately impacts the adhesive and mechanical properties of the cell.

Two models of cadherin signaling are presented, generally referred to as “transcriptional co-activator sequestration” versus “kinase inhibition” models. For reasons that are largely historical in nature, the former mode is better appreciated since most cytoplasmic “peripheral” components of the cadherin complex (i.e., catenins) also localize to the nucleus to directly impact gene expression. Evidence that cadherins interact with transcriptional co-activators has long suggested a simple way to coordinate adhesion with changes in transcription, however there are problems with this model that merit deeper discussion. It is also clear that cadherin-based adhesion can strongly impact various growth factor receptor kinase signaling cascades, although clear molecular models for explaining these findings have yet to emerge. By discussing the differences between these two modes of cadherin signaling, we hope to build a conceptual framework for thinking about adhesion signaling.

Type

β-Catenin is a Dual-Function Adhesion/Transcriptional Co-Activator Protein

Cadherins as Stoichiometric Inhibitors of β-Catenin Signaling

Evidence for β-Catenin “Release” from the Junction and Nuclear Signaling

Cadherin-Based Adhesion can Limit β-Catenin Signaling Catalytically

Cadherin Tail Clipping and Nuclear Signaling: The Notch Paradigm

Armadillo-Repeat Catenin Proteins in Adhesion and Transcription

E-cadherin Mutations in Human Tumors and Implications for Critical Functions

Transmitting Diverse Signals from Cadherin-Based Contacts

E-Cadherin-Dependent Inhibition of Growth Factor Receptor Signaling

The Cadherin/Catenin Complex as a Key Regulator of the Hippo/Warts Signaling Pathway