PCSK6

What is PCSK6 Protein?

The PCSK6 protein, also known as Proprotein Convertase Subtilisin/Kexin Type 6, is an enzyme encoded by the PCSK6 gene on human chromosome 15. It is a calcium-dependent serine endoprotease, part of a family that processes precursor proteins into their active forms. PCSK6 is involved in various biological processes such as activating growth factors like TGFβ that are crucial for embryonic development and the establishment of left-right body asymmetry. It's also linked to brain structural asymmetries, handedness, and cardiovascular regulation through corin activation. Clinical studies suggest that mutations or dysregulation in PCSK6 can contribute to conditions like hypertension, tumor progression, and developmental disorders, highlighting its significance in both normal physiology and disease.

What is the Function of PCSK6 Protein?

PCSK6, or Proprotein Convertase Subtilisin/Kexin Type 6, is quite the multitasker in the world of enzymes. Essentially, it acts as a biological "scissor," snipping precursor proteins so they can mature into their active forms. Without PCSK6, many proteins would remain in their inactive stages, unable to perform their duties. This enzyme plays a significant role during embryonic development by influencing growth factors that shape the body's layout and ensure organs develop correctly on each side of the body. As it turns out, PCSK6 doesn’t clock out after the embryonic phase; it’s also involved in regulating blood pressure. It does this by activating a specific protein that helps the heart control sodium levels—quite a busy protein indeed. Research even hints that variations of PCSK6 activity might be linked to conditions such as certain cancers and high blood pressure, making it a target of interest for medical research into these ailments. So, PCSK6 isn't just another protein; it’s a crucial player in keeping many bodily functions running smoothly.

PCSK6 Related Signaling Pathway

PCSK6, or Proprotein Convertase Subtilisin/Kexin Type 6, is a multifaceted enzyme that plays a crucial role in various signaling pathways, primarily by processing precursor proteins into their active forms. This processing is pivotal in cellular communication and signal transduction, affecting a wide array of physiological processes. One prominent pathway associated with PCSK6 involves the activation of proteins essential for cardiovascular health, particularly in regulating blood pressure. By activating corin—a protein involved in the conversion of pro-atrial natriuretic peptide—PCSK6 indirectly influences sodium excretion and blood pressure homeostasis. PCSK6 also contributes to developmental pathways by modifying transforming growth factors that guide embryonic development and tissue differentiation. The enzyme's role in the remodeling of the extracellular matrix through substrates like transforming growth factor-beta (TGF-β) highlights its importance in cellular growth and repair mechanisms. Aberrant PCSK6 activity has been linked to diseases such as hypertension and certain cancers, underscoring its potential as a therapeutic target. Understanding PCSK6's involvement in these pathways could lead to innovative treatments for related conditions.

PCSK6 Related Diseases

PCSK6, or Proprotein Convertase Subtilisin/Kexin Type 6, is linked to several health conditions due to its role in activating proteins by processing their precursors. It's notably involved in cardiovascular health, affecting blood pressure regulation through the activation of corin, essential for heart function. Disruptions in PCSK6 activity can lead to hypertension. Additionally, PCSK6 is crucial in embryonic development, influencing body symmetry and organ positioning. Mutations in PCSK6 may result in developmental disorders and asymmetries. It also has potential connections to neurological conditions and traits like handedness, reflecting its broader impact on human health. Understanding these associations could lead to new therapeutic strategies.

Bioapplications of PCSK6

PCSK6, known for its critical role in activating precursor proteins, has promising bioapplications in various fields. In gene therapy, its precise processing ability is explored to correct genetic disorders linked to protein misprocessing. In regenerative medicine, PCSK6's influence on cell differentiation aids tissue engineering and healing. Furthermore, the enzyme is being investigated for targeted drug delivery, aiming to activate drugs specifically in desired tissues, thereby minimizing side effects. In cancer research, understanding its role in tumor growth presents new therapeutic targets. These applications highlight PCSK6's potential in enhancing healthcare technologies and treatments.

Case Study 1: Weishaupt C. et al. Acta Derm Venereol. 2020

Despite new treatments, melanoma still poses challenges. PACE4/PCSK6, a prohormone convertase, may be a key player in melanoma growth. In lab studies, boosting PACE4 in melanoma cells increased their growth, enzyme production, and movement. In mice, higher PACE4 levels led to more aggressive tumors. Many human melanoma samples showed PACE4 activity, suggesting it's crucial in driving the cancer's aggressiveness.

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  Fig1. PACE4 protein levels in NHM and human melanoma cell lines, as shown by Western immunoblotting.
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  Fig2. Analysis of tumour cell migration of the single clone A375.pCI. rPACE4.1 and vector-alone-transfected cells.

Case Study 2: Wu X. et al. Redox Biol. 2022

AKAP12 is a scaffold protein key for cell structure and signaling, but its role in liver injury isn't clear. Research shows that losing AKAP12 in acute liver injury triggers the PI3K/AKT pathway, boosts PCSK6 expression, and ramps up inflammation via macrophages. Silencing PCSK6 was found to lessen liver damage in AKAP12-deficient mice, highlighting PCSK6’s importance in liver injury. Additionally, STAT3 and AKT levels went up in chronic liver damage in these mice. Overall, AKAP12 seems to protect against liver injury by inhibiting the PI3K/AKT/PCSK6 pathway, paving the way for potential new treatments.

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  Fig3. WB detection of PCSK6 protein expression.
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  Fig4. Expression of PCSK6, PI3K, and AKT after AKAP12 silencing.

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  Fig1. PCSK6 as a key regulator of SMC function in vascular remodeling. (Urszula Rykaczewska, 2020)
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  Fig2. The proenzyme form of MASP-3 (pro-MASP-3) is constitutively activated in the blood by PCSK6 (PACE4). (József Dobó, 2022)

PCSK6 has several biochemical functions, for example, endopeptidase activity,heparin binding,nerve growth factor binding. Some of the functions are cooperated with other proteins, some of the functions could acted by PCSK6 itself. We selected most functions PCSK6 had, and list some proteins which have the same functions with PCSK6. You can find most of the proteins on our site.

Function	Related Protein
nerve growth factor binding	FURIN,SORT1,NGFR,NGFRB,NTRK1
endopeptidase activity	TRAPPC12,KLK1B8,KLK1B26,ADAMTS3,KLK1B5,TPP1,ACE2,PSMA1,PSMB5,KLK1B22
serine-type endopeptidase activity	PREP,MASP1,LOC100686744,KLK1B3,LONP1,C1RA,TMPRSS11F,PRSS3,LTF,CFD
heparin binding	COL13A1,OGN,CCL8,NRP1,PRELP,Epy,SLIT2,CTGFB,CCL23,ANG

PCSK6 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 PCSK6 here. Most of them are supplied by our site. Hope this information will be useful for your research of PCSK6.

RXRB;CACNA1A;treB