Novel protein-tyrosine kinase gene (hck) preferentially expressed in cells of hematopoietic origin.

Abstract

Protein-tyrosine kinases are implicated in the control of cell growth by virtue of their frequent appearance as products of retroviral oncogenes and as components of growth factor receptors. Here we report the characterization of a novel human protein-tyrosine kinase gene (hck) that is primarily expressed in hematopoietic cells, particularly granulocytes. The hck gene encodes a 505-residue polypeptide that is closely related to pp56kk, a lymphocyte-specific protein-tyrosine kinase. The exon breakpoints of the hck gene, partially defined by using murine genomic clones, demonstrate that hck is a member of the src gene family and has been subjected to strong selection pressure during mammalian evolution. High-level expression of hck transcripts in granulocytes is especially provocative since these cells are terminally differentiated and typically survive in vivo for only a few hours. Thus the hck gene, like other members of the src gene family, appears to function primarily in cells with little growth potential.Specific phosphorylation of proteins on tyrosine residues was first detected in lysates of cells infected with acutely transforming retroviruses and is now known to be mediated by two related but distinct classes of protein-tyrosine kinases (24). Members of the first class are integral membrane proteins and are, in many cases, receptors for cellular growth factors. The receptors for epidermal growth factor (15), platelet-derived growth factor (17), insulin, insulinlike growth factor 1 (52), and colony stimulating factor 1 (42, 45) all exhibit ligand-stimulated protein-tyrosine kinase activity and, along with the proteins encoded by the oncogenes neu and trk, are members of this first group.The second class of protein-tyrosine kinases, exemplified by the 60-kilodalton product of the c-src gene, includes molecules that are often membrane associated but lack an extracellular domain (24). Although the function of these molecules is in no case known, the majority were first identified as cellular homologs of retroviral oncogenes, for example, c-src, c-fgr, and c-abl (5, 54). Thus, it is attractive to view all of the protein-tyrosine kinases, those that are integral membrane proteins as well as those that are simply membrane associated, as components of signal transduction systems regulating cell proliferation.At the same time, several lines of evidence indicate that the membrane-associated protein-tyrosine kinases regulate aspects of differentiation in postmitotic cells. In vertebrate (9, 31, 53), as well as invertebrate (47)

Hematopoietic cells express two forms of lyn kinase differing by 21 amino acids in the amino terminus.

“…The expression pattern of the lyn protein in hematopoietic cells differs from that of other src-related protein tyrosine kinases that are expressed in hematopoietic cells (24). In particular, Ick is expressed in T-lymphoid cells and natural killer cells and to a lesser degree in some B cells (8), blk is expressed in B-lymphoid cells (20), fgr is expressed in normal monocytic cells and granulocytes (37), and hck is expressed in monocytes and granulocytes and at low levels in some B cells (41 in a signal transduction pathway common to myeloid cells and B-lymphoid cells. In this regard, it is interesting to note that several membrane molecules are expressed in a similar pattern on hematopoietic cells, including the receptors for complement components and the Fc portion of immunoglobulin molecules (31,33).…”

Putative tyrosine kinases expressed in K-562 human leukemia cells.

“…Sequence analysis resulted in the identification of exclusively tyrosine kinaserelated sequences, representing altogether 14 distinct cDNAs, called JTK1-14. Six of the JTK clones were identified as known tyrosine kinase cDNAs, namely those encoding the lyn (23), hck (24,25), c-abl (26) Several tyrosine kinase-specific sequence motifs are present in these sequences: the sequence DLAAN or DLAARN (in one-letter code) beginning with the amino acid sequence derived from the left-hand oligonucleotide is present in all JTK clones. This is a characteristic feature used to distinguish tyrosine kinases from serine and threonine kinases that have the DLKPEN consensus sequence in this region (3).…”

Distribution of c-yes-1 gene product in various cells and tissues

“…In fact it was recently demonstrated that non-receptor-type kinases encoded by the src gene or yesrelated oncogenes are associated with not only cell growth but also cell differentiation (Gee et al, 1986;Golden et al, 1986;Marth et al, 1987;Ziegler et al, 1987).…”