Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function

Holtz, Alexander M.; Griffiths, Samuel C.; Davis, Samantha; Bishop, B.; Siebold, Christian; Allen, Benjamin L.

doi:10.1084/jem.2127oia55

Cited by 10 publications

(17 citation statements)

References 48 publications

(60 reference statements)

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“…Hedgehog (Hh): Hh-mediated signalling has been shown to correlate directly with cell cycle regulation [49]. The Hh pathway can be modulated in some settings by HS where the binding of Hh to HS followed by its release upon HPSE activity can lead to increased Hh signalling and an aggressive cancer phenotype [50][51][52][53][54]. Wnt: HPSE has been shown to mediate Wnt signalling in cancer settings via studies on medulloblastoma and pancreatic cancer [55,56].…”

Section: Sustaining Proliferative Signallingmentioning

confidence: 99%

Heparanase and the hallmarks of cancer

Jayatilleke

Hulett

2020

J Transl Med

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Heparanase is the only mammalian enzyme that cleaves heparan sulphate, an important component of the extracellular matrix. This leads to the remodelling of the extracellular matrix, whilst liberating growth factors and cytokines bound to heparan sulphate. This in turn promotes both physiological and pathological processes such as angiogenesis, immune cell migration, inflammation, wound healing and metastasis. Furthermore, heparanase exhibits non-enzymatic actions in cell signalling and in regulating gene expression. Cancer is underpinned by key characteristic features that promote malignant growth and disease progression, collectively termed the ‘hallmarks of cancer’. Essentially, all cancers examined to date have been reported to overexpress heparanase, leading to enhanced tumour growth and metastasis with concomitant poor patient survival. With its multiple roles within the tumour microenvironment, heparanase has been demonstrated to regulate each of these hallmark features, in turn highlighting the need for heparanase-targeted therapies. However, recent discoveries which demonstrated that heparanase can also regulate vital anti-tumour mechanisms have cast doubt on this approach. This review will explore the myriad ways by which heparanase functions as a key regulator of the hallmarks of cancer and will highlight its role as a major component within the tumour microenvironment. The dual role of heparanase within the tumour microenvironment, however, emphasises the need for further investigation into defining its precise mechanism of action in different cancer settings.

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Section: Sustaining Proliferative Signallingmentioning

confidence: 99%

Heparanase and the hallmarks of cancer

Jayatilleke

Hulett

2020

J Transl Med

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“…The expression of Ptc/Ptch and Hhip1 is induced upon Hh pathway activation, creating a negative-feedback loop. In contrast to Ptc/ Ptch, Hhip1 also exists in a secreted form that inhibits Hh signalling non-autonomously (Holtz et al, 2015).…”

Section: Hh Signal Receptionmentioning

confidence: 99%

Hedgehog signalling

2016

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The Hedgehog (Hh) signalling pathway is one of the key regulators of metazoan development. Hh proteins have been shown to play roles in many developmental processes and have become paradigms for classical morphogens. Dysfunction of the Hh pathway underlies a number of human developmental abnormalities and diseases, making it an important therapeutic target. Interest in Hh signalling thus extends across many fields, from evo-devo to cancer research and regenerative medicine. Here, and in the accompanying poster, we provide an outline of the current understanding of Hh signalling mechanisms, highlighting the similarities and differences between species.

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“…Whereas HSPGs facilitate extracellular Hh transport, the vertebrate protein Hhip antagonizes it (Chuang & McMahon 1999, Kwong et al 2014. Initially believed to be a transmembrane (Chuang & McMahon 1999) or GPI-anchored protein (Bosanac et al 2009), Hhip was recently shown to be secreted and to associate with the extracellular matrix by binding HSPGs (Holtz et al 2015). Hhip is composed of a basic CRD, a six-bladed beta propeller domain, and two EGF-like repeats.…”

Section: Hhip: An Extracellular Hedgehog Ligand Antagonistmentioning

confidence: 99%

Sending and Receiving Hedgehog Signals

Petrov

Wierbowski

Salic

2017

Annu. Rev. Cell Dev. Biol.

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Communication between cells pervades the development and physiology of metazoans. In animals, this process is carried out by a relatively small number of signaling pathways, each consisting of a chain of biochemical events through which extracellular stimuli control the behavior of target cells. One such signaling system is the Hedgehog pathway, which is crucial in embryogenesis and is implicated in many birth defects and cancers. Although Hedgehog pathway components were identified by genetic analysis more than a decade ago, our understanding of the molecular mechanisms of signaling is far from complete. In this review, we focus on the biochemistry and cell biology of the Hedgehog pathway. We examine the unique biosynthesis of the Hedgehog ligand, its specialized release from cells into extracellular space, and the poorly understood mechanisms involved in ligand reception and pathway activation at the surface of target cells. We highlight several critical questions that remain open.

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Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function

Cited by 10 publications

References 48 publications

Heparanase and the hallmarks of cancer

Heparanase and the hallmarks of cancer

Hedgehog signalling

Sending and Receiving Hedgehog Signals

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