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Volume 16, Number 24, Issue of December 15, 1996 pp. 7821-7831
Copyright ©1996 Society for Neuroscience

STEP₆₁: A Member of a Family of Brain-Enriched PTPs Is Localized to the Endoplasmic Reticulum

Received July 22, 1996; revised Sept. 16, 1996; accepted Sept. 24, 1996.

Abel Bult¹, Feisha Zhao¹, Ronald Dirkx Jr.², Ela Sharma³, Erika Lukacsi⁴, Michele Solimena², Janice R. Naegele^{1, 4}, and Paul J. Lombroso¹

¹ Child Study Center and ² Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, ³ Department of Biology, Rutgers University, New Brunswick, New Jersey 08903, and ⁴ Program in Neuroscience and Behavior, Department of Biology, Wesleyan University, Middletown, Connecticut 06459

The STEP family of protein tyrosine phosphatases is highly enriched within the CNS. Members of this family are alternatively spliced to produce both transmembrane and cytosolic variants. This manuscript describes the distinctive intracellular distribution and enzymatic activity of the membrane-associated isoform STEP₆₁. Transfection experiments in fibroblasts, as well as subcellular fractionations, sucrose density gradients, immunocytochemical labeling, and electron microscopy in brain tissue, show that STEP₆₁ is an intrinsic membrane protein of striatal neurons and is associated with the endoplasmic reticulum. In addition, structural analysis of the novel N-terminal region of STEP₆₁ reveals several motifs not present in the cytosolic variant STEP₄₆. These include two putative transmembrane domains, two sequences rich in Pro, Glu, Asp, Ser, and Thr (PEST sequences), and two polyproline-rich domains. Like STEP₄₆, STEP₆₁ is enriched in the brain, but the recombinant protein has less enzymatic activity than STEP₄₆. Because STEP₄₆ is contained in its entirety within STEP₆₁ and differs only in the extended N terminus of STEP₆₁, this amino acid sequence is responsible for the association of STEP₆₁ with membrane compartments and may also regulate its enzymatic activity.

Key words: protein tyrosine phosphatase; intracellular PTP; basal ganglia; alternative splicing; SH3 domain; polyproline domain; PEST sequence; signal transduction; endoplasmic reticulum

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