Development - Hedgehog signaling

Hedgehog signaling

The Hedgehog (HH) family of proteins control cell growth, survival, and fate, and pattern almost every aspect of the vertebrate body plan [1], [2], [3]. Sonic hedgehog homolog (SHH) activation requires several steps: autocleavage, Cholesterol binding, palmitoylation by Hedgehog acyltransferase (HHAT) [2], [4], [5], [6]. Activated SHH is transported by binding to Dispatched homolog 1 (DISP1) into extracellular region [7]. Growth arrest-specific 1 (GAS1) [8], Boc homolog (BOC), Cdon homolog (CDON) [9], [10] bind to SHH and activate HH signaling. Ribosomal protein L29 (HIP) binds to SHH, Indian hedgehog homolog (IHH), Desert hedgehog homolog (DHH) and inhibits HH signaling pathway [11].

SHH, IHH, DHH are members of HH family, which induce HH signaling pathway activation by binding to Patched homolog 1 (PTHC1) [3], [12], [13]. Ligand-induced inhibition of PTCH1 leads to activation of Smoothened homolog (Smoothened) [14]. Smoothened function depends on intraflaggelar transport proteins Arrestin, beta 1 and 2 (Beta-arrestin1 and 2), Kinesin family member 3A (KIF3A), which bind to and activate Smoothened [15]. Adrenergic, beta, receptor kinase 1 (GRK2) phosphorylates Smoothened and induces it activation [16], [17]. Under SHH activation Smoothened can induce Ubiquitin-dependent degradation of Suppressor of fused homolog (SUFU), main regulator of HH signaling pathway [18], [19], [20]. Inhibition of SUFU leads to activation of GLI family zinc finger 3 and 2 (GLI-3 and GLI-2) transcriptional activity [1], [21]. GLI-2 and GLI-3 promote transcription of GLI family zinc finger 1 (GLI-1) [22], [23]. GLI-1 activates target genes, involved in regulation of HH signaling: PTCH1, HIP [24]. Activated GLI-2 and GLI-3 can be ubiquitinated by Cul3/SPOP/Rbx1 E3 ligase and then undergo 26S proteasome (20S core)-dependent degradation [25], [26].

SHH-activated Smoothened binds to Kinesin family member 27 (KIF27) and promotes activation of Serine/threonine kinase 36, fused homolog (STK36) [1], [27], [28]. Cell division cycle 37 homolog (CDC37) in cooperation with Heat shock protein 90kDa (HSP90) binds to and induces STK36 [27]. STK36 activates GLI-2, GLI-1 and inhibits SUFU [29].

SHH -induced Smoothened activates Mitogen-activated protein kinase kinase kinase 10 (MLK2(MAP3K10)) activity [13]. MLK2(MAP3K10) inhibits Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 2 (DYRK2) [30], [31]. DYRK2 phosphorylation of GLI-2, GLI-3 induces degradation of transcription factors [21], [30].

In absence of HH ligand Protein kinase, cAMP dependent, catalytic (PKA-cat (cAMP-dependent)) phosphorylates GLI-3 [32] and induces several consecutive processes: SUFU binds to GLI-3 and promotes GLI-3 phosphorylation by Glycogen synthase kinase 3 beta (GSK3 beta) [33], Casein kinase I phosphorylates GLI-3 [34], Beta-transducin repeat containing (beta-TrCP) in complex with Cullin 1 binds to phosphorylated GLI-3 and promotes Ubiquitin-dependent processing of GLI-3 by 26S proteasome (20S core) into GLI family zinc finger 3, repressor form (GLI-3R) [26], [35]. GLI-3R acts as co-repressor of transcription: GLI-3R and SUFU bind to Catenin (cadherin-associated protein), beta 1, 88kDa (Beta-catenin) and inhibit it function [36], [37], [38].

On the other hand in absence of ligand PKA-cat (cAMP-dependent), GSK3 beta, Casein kinase I phosphorylate GLI-2 and induce Cul1/Rbx1 E3 ligase-dependent 26S proteasome (20S core) degradation of GLI-2 [13], [39], [40]. Degradation of GLI-1 in absence of HH signal is promoted by Numb homolog (NUMB) [41]. NUMB binds to GLI-1 and induce Itchy E3 ubiquitin protein ligase homolog (Itch)-dependent proteasome degradation of GLI-1. SUFU binds to and inhibits GLI-1, GLI-2 and GLI-3 activity [19], [25]. SUFU also recruits SIN3 homolog A, transcription regulator (Sin3A)/Histone deacetylase (HDAC) complex through interaction with Sin3A-associated protein, 18kDa (SAP18) to repress GLI-1 and enhance GLI-3R activity [42], [43].

Cyclin-dependent kinase 11B (CDK11) binds to and inhibits SUFU thereby activating Hedgehog signaling [44].

SHH inhibits PTCH1-induced inhibition of Cyclin B1, results in activation of cell proliferation [45].

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