Characterization of NKIP: a novel, Na+/K+-ATPase interacting protein mediates neural differentiation and apoptosis

Exp Cell Res. 2008 Feb 1;314(3):463-77. doi: 10.1016/j.yexcr.2007.11.013. Epub 2007 Nov 24.


Cellular differentiation and programmed cell death are tightly controlled to maintain tissue homeostasis and proper organ function. In a screen for apoptosis specific gene products, we isolated an immediate early apoptosis response gene from myelomonocytic stem cells that appears to play a key regulatory role in a number of cell types and may be of particular importance in cells of the central nervous system. The gene's 28 kDa protein product interacts with the C-terminal ectodomain of the Na+/K+-ATPase (NKA) beta 1 subunit and was therefore named NKIP (NKA Interacting Protein). NKIP is coexpressed with NKA, localizes to lysosomes and the endoplasmic reticulum and is predominantly expressed in excitable tissues including polarized epithelia and the central nervous system. NKIP has been characterized as an endogenous suppressor of the NKA as reduction of NKIP in PC12 cells significantly increases NKA activity. In pluripotent NT2 progenitor cells, NKIP induced rapidly K+-level-dependent cell death. NKIP overexpression induced growth factor-independent neurite outgrowth, which was associated with MEK-independent phosphorylation of the transcription factor ERK1/2. Thus, we have identified NKIP as an important novel protein that interacts to the NKA complex, influencing cellular ion balance, induction of apoptosis and neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Differentiation / genetics*
  • Cell Line
  • Cell Line, Tumor
  • Cells, Cultured
  • Central Nervous System / cytology
  • Central Nervous System / embryology*
  • Central Nervous System / metabolism
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / ultrastructure
  • Female
  • Humans
  • Immediate-Early Proteins / genetics
  • Immediate-Early Proteins / metabolism*
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Neurites / metabolism
  • Neurites / ultrastructure
  • PC12 Cells
  • Potassium / metabolism
  • Protein Binding
  • Protein Subunits / metabolism
  • Rats
  • Sodium-Potassium-Exchanging ATPase / metabolism*
  • Stem Cells / cytology
  • Stem Cells / metabolism*


  • Apoptosis Regulatory Proteins
  • Immediate-Early Proteins
  • Protein Subunits
  • Sodium-Potassium-Exchanging ATPase
  • Potassium