Primary Cilia and Coordination of Receptor Tyrosine Kinase (RTK) and Transforming Growth Factor β (TGF-β) Signaling

Abstract

Since the beginning of the millennium, research in primary cilia has revolutionized our way of understanding how cells integrate and organize diverse signaling pathways during vertebrate development and in tissue homeostasis. Primary cilia are unique sensory organelles that detect changes in their extracellular environment and integrate and transmit signaling information to the cell to regulate various cellular, developmental, and physiological processes. Many different signaling pathways have now been shown to rely on primary cilia to function properly, and mutations that lead to ciliary dysfunction are at the root of a pleiotropic group of diseases and syndromic disorders called ciliopathies. In this review, we present an overview of primary cilia-mediated regulation of receptor tyrosine kinase (RTK) and transforming growth factor b (TGF-b) signaling. Further, we discuss how defects in the coordination of these pathways may be linked to ciliopathies.

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

“…The activity of several signaling pathways, including those mediated by receptor tyrosine kinases (like TβRI/II), Wnt, Notch, mTOR, and Shh (60, 61), is coordinated within cell surface projections called primary cilia. Thus, various biological and physiological functions depend on the formation of functional primary cilia.…”

Gates for soluble and membrane proteins, and two trafficking systems (IFT and LIFT), establish a dynamic ciliary signaling compartment

“…GLI is no longer processed by the proteasome and PKA into an inhibitor, instead acting as a transcriptional activator upon Hh stimulation [19,20,26]. The cilium therefore facilitates the spatial separation of pathway components, promoting a rapid, regulated response not requiring translation or long-distance protein 84 Cell organelles transport [17]. This response appears to be mediated by the IFT-BBSome system (see below and Figure 1).…”

“…As regulatable cellular antenna, cilia concentrate signaling proteins within the organelle (e.g., cGMP/ cAMP signal transduction components), or spatially separate, over a small distance, different components of the same signalling pathway (e.g., Hedgehog, Insulin/IGF and TGF-b pathways) [17,18,27] (Figure 1). …”

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

“…). Accumulating evidence has implicated primary cilia, which are nonmotile versions of the organelle found in a single copy on most cell types in our body, in regulation of multiple cellular signalling pathways during development and in the adult, including Hedgehog and G‐protein‐coupled receptor (GPCR) signalling , as well as WNT and planar cell polarity (PCP) , receptor tyrosine kinase (RTK) , Notch , TGF‐β/BMP , Hippo , mTOR and polycystin signalling . The ability of primary cilia to regulate signalling relies on carefully orchestrated trafficking of membrane receptors and other signal transducers into and out of the organelle, both constitutively and in response to specific cellular and environmental stimuli.…”