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Hedgehog Signaling

刺猬(Hh)因子信号在不同分类学分类的脊索动物中高度保留。对于胚胎的发育来说其至关重要。第一次成功描绘和表征刺猬因子途径是在黑腹果蝇中。在哺乳动物中,Hh因子信号在胚胎早期形成以及具体器官和组织形态形成的过程中调节细胞命运、组织极性和样式。随后就在大多数成熟组织中不工作了,但是在有损伤的情况下可以重新激活来促进修复和再生。

不同的Hh因子配位体,包括:同系物音刺猬(SHH)因子、印度刺猬(IHH)因子和沙漠刺猬因子(DHH),已经生产出来作为在分泌之前经过自催化切割、C端胆固醇附着、N端棕榈酰化的前体。通过果蝇脱出(Disp)蛋白的同系物调节成熟配位体的释放和细胞外积聚。分泌的Hh因子配位体与受体同系物(PTCH1、PTCH2)连接刺激了信号网络:跨膜受体SMO上PTCH的抑制效果减轻,从而激活胶质瘤相关致癌基因(GLI)转录因子。

这个过程重要的专门结构是基于微管的初级纤毛。在没有未处理的Hh因子信号的情况下,未激活GLI蛋白及其调节因子SUFU集中在初级纤毛的远端。连接Hh因子配位体后,PTCH迁移到细胞表面,使得SMO易位到初级纤毛以及向下调节SUFU成为可能。很多结构上重要的初级纤毛蛋白也对Hh因子信号级联有调节作用。

畸变的Hh/GLI调节造成重性组织紊乱以及各种进展期癌症的发展。Hh/GLI级联也和干性基因的调节和癌症干细胞的存活有关。

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Hedgehog

Hh Processing

PRKACG (Protein Kinase, CAMP-Dependent, Catalytic, gamma):

PRKAR1A - Protein Kinase, CAMP-Dependent, Regulatory, Type I, alpha (Tissue Specific Extinguisher 1):

PRKAR1B (Protein Kinase, CAMP-Dependent, Regulatory, Type I, beta):

PRKAR2A - Protein Kinase, CAMP-Dependent, Regulatory, Type II, alpha:

PRKAR2B (Protein Kinase, CAMP-Dependent, Regulatory, Type II, beta):

Hh Receptors

Hh Effectors

Primary Cilium

KIF7 (Kinesin Family Member 7):

EVC2 - Ellis Van Creveld Syndrome 2:

DYNC2H1 (Dynein, Cytoplasmic 2, Heavy Chain 1):

DYNC2LI1 (Dynein, Cytoplasmic 2, Light Intermediate Chain 1):

IFT43 (Intraflagellar Transport 43 Homolog):

WDR35 (WD Repeat Domain 35):

TTC21B (Tetratricopeptide Repeat Domain 21B):

IFT140 - Intraflagellar Transport 140 Homolog (Chlamydomonas):

IFT20 (Intraflagellar Transport 20 Homolog):

IFT27 (Intraflagellar Transport 27 Homolog (Chlamydomonas)):

IFT46 (Intraflagellar Transport 46 Homolog (Chlamydomonas)):

TRAF3IP1 (TNF Receptor-Associated Factor 3 Interacting Protein 1):

IFT57 (Intraflagellar Transport 57 Homolog):

TTC30B (Tetratricopeptide Repeat Domain 30B):

IFT74 (Intraflagellar Transport Protein 74 Homolog):

IFT80 (Intraflagellar Transport 80 Homolog (Chlamydomonas)):

IFT81 (Intraflagellar Transport 81 Homolog):

IFT88 (Intraflagellar Transport 88 Homolog):

TTC8 (Tetratricopeptide Repeat Domain 8):

Hh Regulators

DISP2 (Dispatched Homolog 2 (Drosophila)):

KCTD11 - Potassium Channel Tetramerisation Domain Containing 11:

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