DHH

What is DHH protein?

DHH (desert hedgehog signaling molecule) gene is a protein coding gene which situated on the long arm of chromosome 12 at locus 12q13. The protein encoded by this gene called DHH, which is a member of the hedgehog family. This protein is predicted to be made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. This protein may be involved in both male gonadal differentiation and perineurial development. The DHH protein is consisted of 396 amino acids and its molecular mass is approximately 43.6 kDa.

What is the function of DHH protein?

The DHH protein is a member of the Hedgehog signaling pathway family, which plays an important role in embryonic development and tissue regeneration. Specifically, DHH activates downstream signal transduction pathways by binding to its receptors, thereby affecting biological processes such as cell proliferation, differentiation, and apoptosis. During the development of male reproductive system, DHH plays an important role in the regulation of testicular development and spermatogenesis. In addition, DHH is involved in the development of other tissues, such as the nervous system and digestive system.

Fig1. DHH regulation of male gonadal development. DHH secreted by the SCs signals through PTCH1 and GLI1 in the LCs to regulate their development and overall organization of the testis cord. (Iman Dilower, 2023)

DHH Related Signaling Pathway

The DHH protein is primarily involved in the Hedgehog signaling pathway, which plays an important role in embryonic development, tissue regeneration, and disease occurrence. DHH activates downstream signal transduction pathways by binding to its receptors, thereby affecting biological processes such as cell proliferation, differentiation and apoptosis. In addition, DHH is also involved in the regulation of other signaling pathways, such as Wnt, Notch, etc., which further affects tissue development and disease occurrence.

DHH Related Diseases

DHH protein-related diseases include diseases of the reproductive system and tumors. In the reproductive system, the abnormal expression of DHH may lead to problems such as male infertility and testicular dysplasia. In addition, some studies have also found that DHH is associated with the occurrence and development of prostate cancer, lung cancer, stomach cancer and other tumors.

Bioapplications of DHH

In tumor therapy, because DHH signaling pathway is closely related to the occurrence and development of a variety of tumors, small molecule inhibitors or antibodies targeting DHH have been developed and entered the clinical trial stage. These drugs prevent tumor growth and metastasis by inhibiting the activation of the DHH signaling pathway.

Case study 1: Duojun Qiu, 2023

This study explored the effects and potential mechanism by which PBX/knotted 1 homeobox 1 (PKNOX1) may exacerbate stomach adenocarcinoma (STAD). In vitro, we measured cell viability, proliferation, migration, and invasion using cell counting kit-8, colony formation, wound healing, and cell migration assays, respectively. Real time qPCR and western blotting assessed the mRNA and protein levels of PKNOX1, Snail, vimentin, N-cadherin, E-cadherin, desert hedgehog (DHH), cyclin D2, glioma-associated oncogene homolog 1, and smoothened.

Downregulation of PKNOX1 inhibited STAD cell viability, proliferation, migration, invasion, and epithelial-mesenchymal transition. Upregulation of TEAD4 promoted colony formation and migration, while these effects were reversed by PKNOX1 depletion. Furthermore, PKNOX1 regulated the activation of the hedgehog signalling pathway at the gene level, as we identified PKNOX1 to be a putative transcription factor for DHH that promotes its expression.

Fig1. PKNOX1 regulates the Hh signalling pathway. DHH, CCND2, GLI1, and SMO protein levels as determined by western blot.

Fig2. Knockdown of PKNOX1 in STAD inhibits cells proliferation, migration, invasion, and EMT in a Hh signalling-dependent manner.

Case study 2: Pilar Chinchilla, 2010

The Hedgehog (Hh) pathway orchestrates developmental and homeostatic angiogenesis. the three Hh isoforms--Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) and Desert Hedgehog (Dhh)--signal through patched-1 (ptCH1) and Smoothened (SMo), to activate the Gli transcription factors with a characteristic rank of potency (Shh >> Ihh > Dhh). To dissect the mechanisms through which Hh proteins promote angiogenesis, the researchers analyzed processes inherent to vessel formation in endothelial cells.

The results showed that none of the Hh ligands were able to induce Gli-target genes in human umbilical vein (HUVeC) or human cardiac microvascular endothelial cells (HMVeC). However, the three Hh proteins promote endothelial cell tubulogenesis in 3D cultures in a SMo- and Gi protein-dependent manner. Consistent with the required cytoskeletal re-arrangement for tubulogenesis, Shh, Ihh and Dhh all stimulated the small GTPase RhoA and the formation of actin stress fibers. In addition to regulating the actin cytoskeleton, the Hh ligands promoted survival through inhibition of the pro-apoptotic effect of PTCH1 in a SMO-independent manner.

Fig3. Tubulogenesis in Matrigel induced by Shh, Ihh and Dhh was quantified as number of tubes and number of nodes per field of n = 3 experiment

Fig4. Actin filaments were stained with phalloidin-rhodamin in serum-starved HUVeC cells (control) and cells stimulated with 1 μg/ml Shh, Ihh and Dhh for 15 min.

DHH has several biochemical functions, for example, calcium ion binding,patched binding,peptidase activity. Some of the functions are cooperated with other proteins, some of the functions could acted by DHH itself. We selected most functions DHH had, and list some proteins which have the same functions with DHH. You can find most of the proteins on our site.

DHH has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with DHH here. Most of them are supplied by our site. Hope this information will be useful for your research of DHH.