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Gene Review

LACRT  -  lacritin

Homo sapiens

 
 
 

Disease relevance of LACRT

Several small trials suggest that only 4 to 5% of the tear proteome appear to be dysregulated in the three forms of dry eye preliminarily examined to date. Downregulated in all three is the glycoprotein and prosecretory mitogen lacritin [1].
 

High impact information on LACRT

  • Here, we report on the identification of a novel secreted glycoprotein, lacritin, that enhances exocrine secretion in overnight cultures of lacrimal acinar cells which otherwise display loss of secretory function . Lacritin also promotes HSG (HeLa) cell proliferation, appears to signal through calcium and tyrosine phoshorylation and is highly restricted in expression [2].
  • Possibly outward flow of lacritin from secretory cells through ducts may generate a proliferative/secretory field as a different unit of cellular renewal in nongermative epithelia where luminal structures predominate [3].
  • Lacritin targets epithelia in an apparently cell-type specific manner via a novel off-on switch involving epithelial heparanase that cleaves heparan sulfate on the cell surface proteoglycan syndecan-1 thus exposing a binding site. The same is not true for syndecan-2 or syndecan-4 [4]. Its mitogenic targeting of human corneal epithelial cells [3] is in keeping with the constitutive expression of heparanase by this epithelium [5].
  • After cell surface ligation, lacritin signaling is initiated. Use of inhibitors and siRNAs suggest that lacritin mitogenic signaling proceeds through Gαi or Gαo to PKCα-PLC-Ca2+-calcineurin-NFATC1 to COX2. Another pathway signals from Gαi or Gαo to PKCα-PLC-PLD to mTOR. Lacritin's dose-reponse curve is bell-shaped [3] .
  • cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimal gland [2].
  • The lacritin gene consists of five exons and maps to 12q13 [2]. Initial PCR experiments suggested no alternative splicing [Ref]. Now it appears from Aceview (based on NEIBank ESTs) that there are four alternative splice forms [6].
 

Biological context of LACRT

  • As an autocrine/paracrine enhancer of the lacrimal constitutive secretory pathway, ductal cell mitogen and stimulator of corneal epithelial cells, lacritin may play a key role in the function of the lacrimal functional unit [2].
  • Lacritin augments unstimulated but not stimulated acinar cell secretion [2].
 

Anatomical context of LACRT

  • Lacritin mRNA and protein are highly expressed in human lacrimal gland, moderately in major and minor salivary glands and slightly in thyroid [2].
  • One group detected lacritin transcripts in 51% (19/37) of the primary invasive breast tumors, in 71% (5/7) of the breast cancer cell lines, and also in 56% (9/16) of the normal breast tissues [7]. This has not been confirmed by Unigene, tissue microarray or multi-tissue dot blot which point to lacritin as one of the most eye-restricted genes (as per α-crystallin) [6]. If present in normal breast, it must be at very low levels.
 

Other interactions of LACRT

  • Examining the tear proteome, 60 tear proteins were identified with high confidence, including well-known abundant tear proteins, and tear-specific proteins such as lacritin and proline-rich proteins [8].
  • In addition to human lacrimal gland, lacritin is also expressed by Meibomian gland [8], cornea and conjunctiva [9], and is detected on contact lenses after wear [10].
  • LACRT maps near but not within the triple A syndome region. Alacrimia in Triple A Syndrome is not due to mutation of LACRT [11].
 

Analytical, diagnostic and therapeutic context of LACRT

  • Small dry eye trials and unpublished preclinical studies suggest that lacritin might have some benefit as a topical therapeutic for dry eye [1].

References

  1. Dry eye and designer ophthalmics. Laurie, G.W., Olsakovsky, L.A., Conway, B.P., McKown, R.L., Kitagawa, K., Nichols, J.J. Optom. Vis. Sci. (2008) [Pubmed]
  2. cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimal gland. Sanghi, S., Kumar, R., Lumsden, A., Dickinson, D., Klepeis, V., Trinkaus-Randall, V., Frierson, H.F., Laurie, G.W. J. Mol. Biol. (2001) [Pubmed]
  3. Restricted epithelial proliferation by lacritin via PKCalpha-dependent NFAT and mTOR pathways. Wang, J., Wang, N., Xie, J., Walton, S.C., McKown, R.L., Raab, R.W., Ma, P., Beck, S.L., Coffman, G.L., Hussaini, I.M., Laurie, G.W. J. Cell Biol. (2006) [Pubmed]
  4. Heparanase deglycanation of syndecan-1 is required for binding of the epithelial-restricted prosecretory mitogen lacritin. Ma, P., Beck, S.L., Raab, R.W., McKown, R.L., Coffman, G.L., Utani, A., Chirico, W.J., Rapraeger, A.C., Laurie, G.W. J. Cell. Biol. (2006) [Pubmed]
  5. Murine ocular heparanase expression before and during infection with Pseudomonas aeruginosa. Berk, R.S., Dong, Z., Alousi, S., Kosir, M.A., Wang, Y., Vlodavsky, I. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  6. The lacrimal gland transcriptome is an unusually rich source of rare and poorly characterized gene transcripts. Ozyildirim, A.M., Wistow, G.J., Gao, J., Wang, J., Dickinson, D.P., Frierson HF, J.r., Laurie, G.W. Invest. Ophthalmol. Vis. Sci. (2005) [Pubmed]
  7. Expression of a novel lacrimal gland gene lacritin in human breast tissues. Weigelt, B., Bosma, A.J., van 't Veer, L.J. J. Cancer Res. Clin. Oncol. (2003) [Pubmed]
  8. Characterisation of human tear proteins using high-resolution mass spectrometry. Zhou, L., Beuerman, R.W., Foo, Y., Liu, S., Ang, L.P., Tan, D.T. Ann. Acad. Med. Singap. (2006) [Pubmed]
  9. Establishment of an appropriate animal model for lacritin studies: cloning and characterization of lacritin in monkey eyes. Nakajima, T., Walkup, R.D., Tochigi, A., Shearer, T.R., Azuma, M. Exp. Eye. Res. (2007) [Pubmed]
  10. Mass spectrometry-based proteomic analyses of contact lens deposition. Green-Church, K.B., Nichols, J.J. Mol. Vis. (2008) [Pubmed]
  11. Genetic separation of the human lacritin gene ("LACRT") and triple A (Allgrove) syndrome on 12q13. Kumar, R., Huebner, A., Laurie, G.W. Adv. Exp. Med. Biol. (2002) [Pubmed]
 
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