Characterization of SHP-1 protein tyrosine phosphatase transcripts, protein isoforms and phosphatase activity in epithelial cancer cells

• Promoters 1 and 2 are used by SHP-1 to transcribe seven mRNAs in epithelial cancer cells.
• SHP-1 transcripts include 5 coding and 2 noncoding transcripts.
• Wild-type or lacking exon 3 transcripts use either promoter 1 or 2.
• Transcripts lacking exons 3 and 4 use only promoter 1 and have increased phosphatase activity.
• Endogenous SHP-1 proteins corresponding to the variant mRNA are found in epithelial cancer cells.

We identified 7 SHP-1 (PTPN6) transcripts using epithelial cancer-derived cell lines. Four were shown to utilize the epithelial promoter 1 to transcribe a full-length, a partial (exon 3) or complete (exons 3 & 4) deletion of the N-SH2 domain, and also a non-coding transcript having a stop codon caused by a frame shift due to intron 2 retention. Three additional transcripts were shown to utilize the hematopoietic promoter 2 to transcribe a full-length, a partial (exon 3) deletion of the N-SH2 domain and a non-coding transcript with intron 2 retention. We show that endogenous proteins corresponding to the open-reading-frame (ORF) transcripts are produced. Using GST-fusion proteins we show that each product of the ORF SHP-1 transcripts has phosphatase activity and isoforms with an N-SH2 deletion have increased phosphatase activity and novel protein–protein interactions. This study is the first to document utilization of promoter 2 by SHP-1 transcripts and a noncoding transcript in human epithelial cells.