Kinase-anchoring proteins in ciliary signal transduction

Abstract

Historically, the diffusion of chemical signals through the cell was thought to occur within a cytoplasmic soup bounded by the plasma membrane. This theory was predicated on the notion that all regulatory enzymes are soluble and moved with a Brownian motion. Although enzyme compartmentalization was initially rebuffed by biochemists as a 'last refuge of a scoundrel', signal relay through macromolecular complexes is now accepted as a fundamental tenet of the burgeoning field of spatial biology. A-Kinase anchoring proteins (AKAPs) are prototypic enzyme-organizing elements that position clusters of regulatory proteins at defined subcellular locations. In parallel, the primary cilium has gained recognition as a subcellular mechanosensory organelle that amplifies second messenger signals pertaining to metazoan development. This article highlights advances in our understanding of AKAP signaling within the primary cilium and how defective ciliary function contributes to an increasing number of diseases known as ciliopathies.

Keywords: AKAP; cilia; protein kinase A.

Figure 1.. Structure of the Primary cilium.

The primary cilium has nine pairs of microtubules but lack the central doublet, forming a hollow cylindrical structure. This figure also shows intraflagellar transport proteins (dynein-2 and kinesis-2) moving cargo into and out of the cilium.

Figure 2.. Normal and defective ciliary signaling.

Normal ciliary signaling is essential for cellular function. A signaling defect or loss of basal body function could lead to cilia-mediated disorders termed as ciliopathies.

Figure 3.. Sonic Hedgehog signaling is antagonized by PKA.

In the absence of hedgehog (Hh), the GPCR patched (Ptch) inhibits Smoothened (Smo). Gpr161 translocates into the cilium and inhibits Gli via a cAMP mediated PKA activation, thereby preventing target gene expression. In contrast, when Hh is available, Patched releases smoothened upon binding to hedgehog. Smoothened activates Gli-mediated target gene expression.

Figure 4.. AKAPs in the ciliary nanodomain and in the mammalian sperm.

(A) AKAPs serve to localize several important kinases, phosphatases, adenylyl cyclases, phosphodiesterases, deacetylases and ion channels near the ciliary compartment. These scaffolding proteins and their binding partners are indicated. (B) AKAPs in the mammalian sperm (adapted from [9]). AKAPs that organize subcellular complexes in different areas of the mammalian sperm are indicated.