Contributions of Noncanonical Smoothened Signaling During Embryonic Development

Abstract

The Sonic Hedgehog (Shh) signaling pathway is active during embryonic development in metazoans, and provides instructional cues necessary for proper tissue patterning. The pathway signal transducing component, Smoothened (Smo), is a G protein-coupled receptor (GPCR) that has been demonstrated to signal through at least two effector routes. The first is a G protein–independent canonical route that signals to Gli transcriptional effectors to establish transcriptional programs specifying cell fate during early embryonic development. The second, commonly referred to as the noncanonical Smo signal, induces rapid, transcription-independent responses that are essential for establishing and maintaining distinct cell behaviors during development. Herein, we discuss contributions of this noncanonical route during embryonic development. We also highlight important open questions regarding noncanonical Smo signal route selection during development, and consider implications of noncanonical signal corruption in disease.

The Role of Smoothened in Cancer

“…SMO activates these molecular switches and targets specific molecules that modulate noncanonical HH signaling responses [ 4 ]. Active Gαi can negatively regulate adenylyl cyclase, thereby inhibiting intracellular cAMP and PKA activity [ 5 ]. SMO-dependent, noncanonical HH signaling also elicits specific cellular responses via the activation of small G-proteins (GTPases).…”

“…CAFs fuel cancer cells via the secretion of soluble factors that trigger metastasis and chemoresistance [ 42 , 43 , 44 , 45 ]. The microenvironment of breast cancer is affected by the type II noncanonical SHH signaling pathway, which can enhance cancer development and metastasis [ 5 , 29 , 46 ]. This process includes extracellular acidification, inflammation and activation of matrix metalloproteases [ 42 , 47 , 48 ].…”

“…The Hedgehog (HH) signaling pathway is a conserved pathway involved in cell growth and tissue patterning [ 1 , 2 , 3 , 4 , 5 ]. It regulates tissue homeostasis and stem cell behaviors, but the pathway becomes quiescent in adult tissues.…”

“…[ 6 ].The canonical HH signaling pathway molecules includes Hedgehog ligands (Sonic hedgehog, Indian hedgehog and Desert hedgehog), PTCH (PTCH-1 and PTCH-2), Smoothened and GLIs (GLI-1, GLI-2 and GLI-3). In the non-canonical SHH signaling pathway, SMO or GLIs are activated by other pathways such as the mammalian target of rapamycin-protein kinase B (mTOR-Akt), protein kinase A (PKA) or Rho [ 1 , 2 , 3 , 4 , 5 ]. SMO is an important target in cancer treatment.…”

Emerging Roles of DYRK Kinases in Embryogenesis and Hedgehog Pathway Control

“…The Hh signaling cascade has been discussed in depth by other excellent reviews of this special issue on embryogenesis (e.g., [ 14 , 15 , 16 , 17 ]). Briefly, the canonical Hh signaling cascade is initiated in the target cell by the Hh ligand binding to the Patched1 receptor (PTCH1) [ 18 , 19 ], a 12-span transmembrane protein located in the ciliary membrane relieving the repression of Smoothened (SMO) [ 20 , 21 ], a 7-span transmembrane protein, which is a member of the G protein-coupled receptor (GPCR) superfamily.…”