4.7 Article

Localization and interaction of NHERF isoforms in the renal proximal tubule of the mouse

期刊

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 285, 期 6, 页码 C1494-C1503

出版社

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00092.2003

关键词

NHE3; Npt2; ezrin; PDZ domains; immunolocalization

资金

  1. NHLBI NIH HHS [HL-62220] Funding Source: Medline
  2. NIDDK NIH HHS [DK-42495, DK-32839, DK-55881] Funding Source: Medline
  3. NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL062220] Funding Source: NIH RePORTER
  4. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK032839, R37DK042495, R01DK042495, R01DK055881, R29DK042495] Funding Source: NIH RePORTER

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In expression systems and in yeast, Na/H exchanger regulatory factor ( NHERF)-1 and NHERF-2 have been demonstrated to interact with the renal brush border membrane proteins NHE3 and Npt2. In renal tissue of mice, however, NHERF-1 is required for cAMP regulation of NHE3 and for the apical targeting of Npt2 despite the presence of NHERF-2, suggesting another order of specificity. The present studies examine the subcellular location of NHERF-1 and NHERF-2 and their interactions with target proteins including NHE3, Npt2, and ezrin. The wild-type mouse proximal tubule expresses both NHERF-1 and NHERF-2 in a distinct pattern. NHERF-1 is strongly expressed in microvilli in association with NHE3, Npt2, and ezrin. Although NHERF-2 can be detected weakly in the microvilli, it is expressed predominantly at the base of the microvilli in the vesicle-rich domain. NHERF-2 appears to associate directly with ezrin and NHE3 but not Npt2. NHERF-1 is involved in the apical expression of Npt2 and the presence of other Npt2-binding proteins does not compensate totally for the absence of NHERF-1 in NHERF-1-null mice. Although NHERF-1 links NHE3 to the actin cytoskeleton through ezrin, the absence of NHERF-1 does not result in a generalized disruption of the architecture of the cell. Thus the mistargeting of Npt2 seen in NHERF-1-null mice likely represents a specific disruption of pathways mediated by NHERF-1 to achieve targeting of Npt2. These findings suggest that the organized subcellular distribution of the NHERF isoforms may play a role in the specific interactions mediating physiological control of transporter function.

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