Distinct roles of first exon variants of the tumor-suppressor Patched1 in Hedgehog signaling.
Patched1 (PTCH1) is one of the key molecules involved in the Hedgehog (HH) signaling pathway and acts as the receptor of HH ligands. Additionally, PTCH1 inhibits the positive signal transductor Smoothened (SMO). Several PTCH1 splice variants are known but the functional differences among them are not clear. Here, we demonstrate the unique biological properties of the PTCH1 isoforms generated by alternative first exon usage. All isoforms examined worked as functional receptors of both Sonic HH and Desert HH. However, the signaling upregulated isoforms PTCH1-1B and -1C inhibited SMO and the pathway transcription factors glioma 1 (GLI1) and GLI2 to a higher extent than PTCH1-1 and -1Ckid. Moreover, in situ hybridizations allowed the detection of the Ptch1 isoforms in specific structures of the developing mouse embryo. Additionally, the differences in the N-terminal tail had a dramatic influence on the steady states of the proteins, with PTCH1-1B and -1C levels being significantly higher than PTCH1-1 and -1Ckid. This implies that the pronounced signaling inhibitory properties of PTCH1-1B and -1C may be mostly due to this high-protein expression rather than to intrinsic functional differences. Thus, our study supports a role of splicing variation and promoter choice for HH signaling regulation.
Shimokawa
T
T
Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden. Tash@biosci.ki.se
Svärd
J
J
Heby-Henricson
K
K
Teglund
S
S
Toftgård
R
R
Zaphiropoulos
P G
PG
D017398:Alternative Splicing; D000818:Animals; D001483:Base Sequence; D047108:Embryonic Development; D005091:Exons; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*; D000071676:Zinc Finger Protein GLI1
D053823:Hedgehog Proteins; D015513:Oncogene Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020033:Protein Isoforms; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D000071676:Zinc Finger Protein GLI1