Hedgehog Signaling in Animal Development and Human Disease 225
terol deficit since lovastatin and 25-hydroxycholesterol, potent inhibitors of the first steps in cholesterol biosynthesis, do not block Shh
signaling (Cooper et al. 1998; Incardona et al. 1998). While the molecular target of these inhibitors is not yet known, a potential candidate may
be Ptc.
12.5.3 Homology of Pte to Sterol-Sensing Proteins
The drugs that inhibit Hh signal reception may be acting on Ptc through
a hydrophobic region of the protein called a sterol-sensing domain. This
domain is a sequence motif containing five potential transmembrane
domains. Sterol sensors are found in proteins involved in cholesterol
metabolism, such as HMG CoA reductase (Kumagai et al. 1995) and
SREBP Cleavage Activating Protein (SCAP) (Nohturfft et al. 1998).
The sterol sensor is required in these proteins for their regulation by
sterols. In the case of HMG CoA reductase, sterols increase protein
degradation (Jingami et al. 1987), while for SCAP, sterols block its
ability to activate a transcriptional response (Nohturfft et al. 1996). The
link of sterol-sensing domains and cholesterol metabolism has recently
been extended to an additional protein called NPC 1.
NPC 1 is implicated as the defective gene in Niemann-Pick Type C 1
syndrome, (Carstea et al. 1997; Loftus et al. 1997). This rare recessive
disorder, which affects both humans and mice, results in the abnormal
accumulation of cholesterol in response to the LDL receptor pathway
(Liscum and Faust 1987; Pentchev et al. 1987). NPCl encodes a large
protein with multiple transmembrane domains and is proposed to move
between intracellular compartments to traffic cholesterol or other components (Carstea et al. 1997; Loftus et al. 1997). NPCl and Ptc share
sequence similarity in many of the predicted membrane-spanning regions including the proposed sterol sensor. The similarity of Ptc to
proteins that respond to or traffic sterols suggests new functions. Ptc
activity may be modulated by sterols and Ptc may regulate signaling in
part by moving between compartments within the cell.
The effects of cholesterol synthesis inhibitors on Shh signaling might
be explained by alterations in Ptc activity as mediated through the sterol
sensor. Several missense mutations in human PTCHI that appear to
abolish its function, map to the putative sterol sensor domain (Chidam-
terol deficit since lovastatin and 25-hydroxycholesterol, potent inhibitors of the first steps in cholesterol biosynthesis, do not block Shh
signaling (Cooper et al. 1998; Incardona et al. 1998). While the molecular target of these inhibitors is not yet known, a potential candidate may
be Ptc.
12.5.3 Homology of Pte to Sterol-Sensing Proteins
The drugs that inhibit Hh signal reception may be acting on Ptc through
a hydrophobic region of the protein called a sterol-sensing domain. This
domain is a sequence motif containing five potential transmembrane
domains. Sterol sensors are found in proteins involved in cholesterol
metabolism, such as HMG CoA reductase (Kumagai et al. 1995) and
SREBP Cleavage Activating Protein (SCAP) (Nohturfft et al. 1998).
The sterol sensor is required in these proteins for their regulation by
sterols. In the case of HMG CoA reductase, sterols increase protein
degradation (Jingami et al. 1987), while for SCAP, sterols block its
ability to activate a transcriptional response (Nohturfft et al. 1996). The
link of sterol-sensing domains and cholesterol metabolism has recently
been extended to an additional protein called NPC 1.
NPC 1 is implicated as the defective gene in Niemann-Pick Type C 1
syndrome, (Carstea et al. 1997; Loftus et al. 1997). This rare recessive
disorder, which affects both humans and mice, results in the abnormal
accumulation of cholesterol in response to the LDL receptor pathway
(Liscum and Faust 1987; Pentchev et al. 1987). NPCl encodes a large
protein with multiple transmembrane domains and is proposed to move
between intracellular compartments to traffic cholesterol or other components (Carstea et al. 1997; Loftus et al. 1997). NPCl and Ptc share
sequence similarity in many of the predicted membrane-spanning regions including the proposed sterol sensor. The similarity of Ptc to
proteins that respond to or traffic sterols suggests new functions. Ptc
activity may be modulated by sterols and Ptc may regulate signaling in
part by moving between compartments within the cell.
The effects of cholesterol synthesis inhibitors on Shh signaling might
be explained by alterations in Ptc activity as mediated through the sterol
sensor. Several missense mutations in human PTCHI that appear to
abolish its function, map to the putative sterol sensor domain (Chidam-