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pathway is conserved to a remarkable degree. Furthermore, several
components involved in Hh signaling are mutated in human tumors and
developmental syndromes, highlighting the importance of this pathway
in disease. Recent work has focused on understanding how the various
components of the Hh pathway receive and transduce the Hh signal to
control cell fate and proliferation decisions. The dissection of the Hh
pathway has provided valuable insights into the basic mechanisms of
development and disease.
12.2 Reception of the Hh Signal
12.2.1 Functional Studies of Pte and Smo
A number of genetic and biochemical experiments have led to a model
of how Hh signaling is received and regulated (Fig. 1). Hh encodes a
secreted glycoprotein that signals to neighboring cells (Lee et al. 1992;
Mohler and Vani 1992; Tabata et al. 1992; Tashiro et al. 1993). Cells that
are competent to receive Hh signals express two critical components, the
membrane proteins Patched (Ptc) and Smoothened (Smo). These proteins have opposing effects on Hh-mediated signaling. Smo, a protein
with sequence hallmarks of G-protein coupled receptors, is a positive
regulator of Hh-induced transcription (Alcedo et al. 1996; van den
Heuvel and Ingham 1996). In contrast, Ptc, a protein with 12 potential
membrane-spanning domains (Hooper and Scott 1989; Nakano et al.
1989), prevents the induction of Hh target genes. In the absence of Hh,
Ptc is proposed to constitutively inhibit transcription (Hidalgo 1991;
Ingham et al. 1991), possibly by associating with and inactivating Smo
(Stone et al. 1996). Hh is thought to induce signaling by binding to Ptc
and thereby relieving the inhibition of Smo (Chen and Strohl 1996;
Marigo et al. 1996; Stone et al. 1996). How Ptc affects Smo, in molecular terms, is not well understood. Apparently, Hh signaling does not
dissociate Smo from Ptc since the two proteins remain together in the
presence ofligand (Stone et al. 1996). While Smo contains an extracellular cysteine-rich domain (CRD) at its N-terminus that could bind a
ligand, none has been identified yet. Smo does not bind Hh (Stone et al.
1996) but it may bind a ligand similar to Wnts, since the CRD of Smo is
E. C. Bailey et al.
pathway is conserved to a remarkable degree. Furthermore, several
components involved in Hh signaling are mutated in human tumors and
developmental syndromes, highlighting the importance of this pathway
in disease. Recent work has focused on understanding how the various
components of the Hh pathway receive and transduce the Hh signal to
control cell fate and proliferation decisions. The dissection of the Hh
pathway has provided valuable insights into the basic mechanisms of
development and disease.
12.2 Reception of the Hh Signal
12.2.1 Functional Studies of Pte and Smo
A number of genetic and biochemical experiments have led to a model
of how Hh signaling is received and regulated (Fig. 1). Hh encodes a
secreted glycoprotein that signals to neighboring cells (Lee et al. 1992;
Mohler and Vani 1992; Tabata et al. 1992; Tashiro et al. 1993). Cells that
are competent to receive Hh signals express two critical components, the
membrane proteins Patched (Ptc) and Smoothened (Smo). These proteins have opposing effects on Hh-mediated signaling. Smo, a protein
with sequence hallmarks of G-protein coupled receptors, is a positive
regulator of Hh-induced transcription (Alcedo et al. 1996; van den
Heuvel and Ingham 1996). In contrast, Ptc, a protein with 12 potential
membrane-spanning domains (Hooper and Scott 1989; Nakano et al.
1989), prevents the induction of Hh target genes. In the absence of Hh,
Ptc is proposed to constitutively inhibit transcription (Hidalgo 1991;
Ingham et al. 1991), possibly by associating with and inactivating Smo
(Stone et al. 1996). Hh is thought to induce signaling by binding to Ptc
and thereby relieving the inhibition of Smo (Chen and Strohl 1996;
Marigo et al. 1996; Stone et al. 1996). How Ptc affects Smo, in molecular terms, is not well understood. Apparently, Hh signaling does not
dissociate Smo from Ptc since the two proteins remain together in the
presence ofligand (Stone et al. 1996). While Smo contains an extracellular cysteine-rich domain (CRD) at its N-terminus that could bind a
ligand, none has been identified yet. Smo does not bind Hh (Stone et al.
1996) but it may bind a ligand similar to Wnts, since the CRD of Smo is