The parathyroid hormone family member TIP39 interacts with sarco/endoplasmic reticulum Ca 2+ - ATPase activity by influencing calcium homoeostasis

Exp Dermatol. 2017 Sep;26(9):792-797. doi: 10.1111/exd.13294. Epub 2017 Apr 21.


Darier disease (DD) is a genetic skin disease that is associated with mutations in the ATP2A2 gene encoding the type 2 sarco/endoplasmic reticulum (ER) Ca2+ - ATPase (SERCA2). Mutations of this gene result in alterations of calcium homoeostasis, abnormal epidermal adhesion and dyskeratosis. Silencing of ATP2A2 in monolayer cell culture of keratinocytes reduces desmoplakin expression at the borders of cells and impacts cell adhesion. Here, we report establishment of a three-dimensional (3D) epidermal model of DD and use this model to evaluate peptide therapy with tuberoinfundibular peptide of 39 residues (TIP39) to normalize calcium transport. Gene silencing of ATP2A2 in keratinocytes grown in a 3D model resulted in dyskeratosis, partial parakeratosis and suprabasal clefts that resembled the histological changes seen in skin biopsies from patients with DD. TIP39, a peptide recently identified as a regulator of keratinocyte calcium transport, was then applied to this ATP2A2-silenced 3D epidermal model. In normal keratinocytes, TIP39 increased [Ca2+ ]i through the inositol trisphosphate (IP3) receptor pathway and stimulated differentiation. In monolayer ATP2A2-silenced keratinocytes, although TIP39 increased cytosolic calcium from the ER, the response was incomplete compared with its control. TIP39 was observed to reduce intercellular clefts of the gene-silenced epidermal model but did not significantly upregulate keratinocyte differentiation genes such as keratin 10 and filaggrin. These findings indicate that TIP39 is a modulator of ER calcium signalling and may be used as a potential strategy for improving aspects of DD.

Keywords: ATP2A2; Darier disease; TIP39; intracellular calcium response; skin barrier disruption.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Calcium / metabolism*
  • Cells, Cultured
  • Darier Disease / metabolism*
  • Endoplasmic Reticulum / metabolism
  • Epidermis / metabolism
  • Humans
  • Keratinocytes / metabolism
  • Neuropeptides / metabolism*
  • Receptor, Parathyroid Hormone, Type 2 / metabolism*
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*


  • Neuropeptides
  • Receptor, Parathyroid Hormone, Type 2
  • tuberoinfundibular peptide 39
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium