# PIP

## Overview
The PIP gene encodes the prolactin-inducible protein (PIP), a glycoprotein predominantly expressed in various exocrine tissues, including the salivary, lacrimal, and mammary glands. PIP is characterized by its immunoglobulin-like fold, which facilitates its interaction with other proteins, such as IgG and CD4, playing a crucial role in immune regulation and mucosal immunity (Hassan2008Prolactin; Hassan2008Crystal). The protein is involved in diverse biological processes, including immune response modulation, cell adhesion, and migration, through its aspartyl protease activity and interaction with components of the extracellular matrix (Sharif2018Pathogenesis). PIP's expression is hormonally regulated, notably by prolactin and androgens, and its dysregulation is implicated in various pathological conditions, including breast and prostate cancers, where it influences tumor progression and patient prognosis (Hassan2008Prolactin; Sauer2023Prognostic). As a potential biomarker for diseases such as keratoconus and breast cancer, PIP represents a significant target for therapeutic interventions and diagnostic applications (Sharif2018Pathogenesis; Sauer2023Prognostic).

## Structure
The prolactin-inducible protein (PIP) is synthesized as a single-chain preprotein consisting of 146 amino acid residues. The mature form of PIP is 118 residues long, following the cleavage of a 28-residue signal peptide, with a theoretical molecular mass of 13 kDa (Hassan2008Prolactin; Hassan2008Crystal). The primary structure includes a potential glycosylation site at Asn77, which is glycosylated with four sugar residues (Hassan2008Crystal). 

The secondary structure of PIP is characterized by a beta-rich composition, consisting of seven antiparallel beta-strands and seven loops, organized into two beta-sheets forming a sandwiched structure (Hassan2008Prolactin; Hassan2008Crystal). This structure is similar to domain 7 of fibronectin type III, despite low sequence identity, indicating functional similarity (Hassan2008Prolactin).

PIP's tertiary structure includes an immunoglobulin-like fold, which is significant for its binding capabilities with molecules such as IgG and CD4 (Hassan2008Prolactin; Hassan2008Crystal). PIP exists in multiple isoforms due to posttranslational modifications and different glycan content, with forms such as dimers in saliva and tetramers in breast cyst fluid and seminal fluid (Hassan2008Prolactin). The protein's structure is stabilized by disulfide linkages formed by its four cysteine residues (Hassan2008Prolactin).

## Function
The prolactin-inducible protein (PIP) is a glycoprotein expressed in various exocrine tissues, including the salivary, lacrimal, and mammary glands. It plays a significant role in immune regulation by binding to CD4+ T cell receptors, potentially modulating immune responses and inhibiting T-lymphocyte apoptosis (Hassan2008Prolactin). PIP is involved in mucosal immunity, being abundant in secretions such as saliva and tears, and contributes to the formation of the enamel pellicle by binding to hydroxyapatite, a major component of tooth enamel (Hassan2008Prolactin).

PIP exhibits aspartyl protease activity, which allows it to degrade fibronectin, a component of the extracellular matrix (ECM). This activity is crucial for cell invasion and viability, as it activates integrin-β1 signaling, influencing cell adhesion and migration (Sharif2018Pathogenesis). The protein also binds to actin, indicating its involvement in cellular interactions and structural stability (Hassan2008Prolactin).

In the context of ocular health, PIP is considered a potential biomarker for keratoconus due to its downregulation in the tears of affected patients, suggesting a role in maintaining corneal structural stability (Sharif2018Pathogenesis). PIP's expression is regulated by hormones such as prolactin and androgens, highlighting its involvement in hormone response pathways (Hassan2008Prolactin).

## Clinical Significance
The prolactin-induced protein (PIP) gene is clinically significant in the context of breast cancer and immune response. Alterations in PIP expression are associated with breast cancer prognosis and treatment response. High PIP expression is linked to better prognosis, longer metastasis-free survival, and enhanced sensitivity to chemotherapy drugs like doxorubicin and paclitaxel, due to increased expression of proapoptotic genes (Sauer2023Prognostic). Conversely, low PIP expression is associated with poorer chemotherapy response and prognosis, particularly in triple-negative breast cancer, which is known for its aggressive nature (Edechi2021The; Sauer2023Prognostic).

PIP also plays a role in immune regulation. Its deficiency can impair Th1 immune responses, leading to increased susceptibility to infections such as Leishmania major. This is due to reduced CD4+ T cell differentiation and impaired macrophage function, which are crucial for effective immune responses (Li2015Deficiency). PIP's involvement in immune responses is further highlighted by its role in dendritic cell maturation and cytokine production, which are essential for robust Th1-cell responses (Li2015Deficiency). These findings underscore the potential of PIP as a biomarker for breast cancer prognosis and as a target for therapeutic interventions in immune-related conditions.

## Interactions
Prolactin Induced Protein (PIP) is involved in various protein-protein interactions, playing significant roles in biological processes such as fertility, immune regulation, and cancer progression. In human seminal plasma, PIP interacts with human serum albumin (HSA), zinc-α-2 glycoprotein (ZAG), and semenogelin I (SEG1) fragments. The interaction with SEG1 fragments is particularly notable as it suggests a role in sperm motility regulation, with SEG1 potentially inhibiting PIP's interaction with ZAG (Tomar2013Interaction). The HSA-PIP complex is stable and may influence sperm capacitation by sequestering PIP, thus affecting sperm motility (Kumar2012Human).

PIP also binds with high affinity to CD4, impacting immune responses by blocking CD4-mediated T cell programmed death and interfering with HIV gp120 binding, which may inhibit syncytium formation (Hassan2008Prolactin). In cancer, PIP is overexpressed in breast and prostate cancers, where it binds to CD4+ T cells and degrades fibronectin, facilitating tumor progression (Hassan2008Prolactin). In estrogen receptor-negative breast cancer, PIP mediates integrin-β1 binding to integrin-linked kinase 1 (ILK1) and ErbB2, promoting cell adhesion and invasion through signaling pathways (Naderi2012Prolactininduced).


## References


[1. (Sauer2023Prognostic) Natalia Sauer, Igor Matkowski, Grażyna Bodalska, Marek Murawski, Piotr Dzięgiel, and Jacek Calik. Prognostic role of prolactin-induced protein (pip) in breast cancer. Cells, 12(18):2252, September 2023. URL: http://dx.doi.org/10.3390/cells12182252, doi:10.3390/cells12182252. This article has 0 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/cells12182252)

[2. (Naderi2012Prolactininduced) Ali Naderi and Michelle Meyer. Prolactin-induced protein mediates cell invasion and regulates integrin signaling in estrogen receptor-negative breast cancer. Breast Cancer Research, July 2012. URL: http://dx.doi.org/10.1186/bcr3232, doi:10.1186/bcr3232. This article has 35 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1186/bcr3232)

[3. (Edechi2021The) Chidalu A. Edechi, Nnamdi M. Ikeogu, Gloria N. Akaluka, Lucas E. L. Terceiro, Mikayla Machado, Enitan S. Salako, Aida F. Barazandeh, Sam K. P. Kung, Jude E. Uzonna, and Yvonne Myal. The prolactin inducible protein modulates antitumor immune responses and metastasis in a mouse model of triple negative breast cancer. Frontiers in Oncology, March 2021. URL: http://dx.doi.org/10.3389/fonc.2021.639859, doi:10.3389/fonc.2021.639859. This article has 12 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fonc.2021.639859)

[4. (Hassan2008Prolactin) Md. I. Hassan, A. Waheed, S. Yadav, T. P. Singh, and F. Ahmad. Prolactin inducible protein in cancer, fertility and immunoregulation: structure, function and its clinical implications. Cellular and Molecular Life Sciences, 66(3):447–459, October 2008. URL: http://dx.doi.org/10.1007/S00018-008-8463-X, doi:10.1007/s00018-008-8463-x. This article has 127 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1007/S00018-008-8463-X)

[5. (Sharif2018Pathogenesis) Rabab Sharif, Sashia Bak-Nielsen, Jesper Hjortdal, and Dimitrios Karamichos. Pathogenesis of keratoconus: the intriguing therapeutic potential of prolactin-inducible protein. Progress in Retinal and Eye Research, 67:150–167, November 2018. URL: http://dx.doi.org/10.1016/j.preteyeres.2018.05.002, doi:10.1016/j.preteyeres.2018.05.002. This article has 85 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.preteyeres.2018.05.002)

[6. (Tomar2013Interaction) Anil Kumar Tomar, Balwinder Singh Sooch, Isha Raj, Sarman Singh, and Savita Yadav. Interaction analysis identifies semenogelin i fragments as new binding partners of pip in human seminal plasma. International Journal of Biological Macromolecules, 52:296–299, January 2013. URL: http://dx.doi.org/10.1016/j.ijbiomac.2012.10.011, doi:10.1016/j.ijbiomac.2012.10.011. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ijbiomac.2012.10.011)

[7. (Li2015Deficiency) Jintao Li, Dong Liu, Zhirong Mou, Olivia C. Ihedioha, Anne Blanchard, Ping Jia, Yvonne Myal, and Jude E. Uzonna. Deficiency of prolactin‐inducible protein leads to impaired th1 immune response and susceptibility to leishmania major in mice. European Journal of Immunology, 45(4):1082–1091, February 2015. URL: http://dx.doi.org/10.1002/eji.201445078, doi:10.1002/eji.201445078. This article has 18 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/eji.201445078)

[8. (Kumar2012Human) Sanjay Kumar, Anil Kumar Tomar, Sudhuman Singh, Mayank Saraswat, Sarman Singh, Tej P. Singh, and Savita Yadav. Human serum albumin as a new interacting partner of prolactin inducible protein in human seminal plasma. International Journal of Biological Macromolecules, 50(2):317–322, March 2012. URL: http://dx.doi.org/10.1016/j.ijbiomac.2011.12.015, doi:10.1016/j.ijbiomac.2011.12.015. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ijbiomac.2011.12.015)

[9. (Hassan2008Crystal) Md. Imtaiyaz Hassan, Sameeta Bilgrami, Vijay Kumar, Nagendra Singh, Savita Yadav, Punit Kaur, and T.P. Singh. Crystal structure of the novel complex formed between zinc α2-glycoprotein (zag) and prolactin-inducible protein (pip) from human seminal plasma. Journal of Molecular Biology, 384(3):663–672, December 2008. URL: http://dx.doi.org/10.1016/j.jmb.2008.09.072, doi:10.1016/j.jmb.2008.09.072. This article has 60 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2008.09.072)