Receptor tyrosine kinase mutations in myeloid neoplasms

The receptor tyrosine kinases (RTKs) are transmembrane enzymes involved in ligand binding and signal transduction at the cell surface. They function in nearly all biological systems and have a broadly conserved molecular topology, which permits activation of intracellular protein kinase activity upon ligand binding. Mutations involving RTK genes occur in both acute and chronic myeloid leukaemias. In this review, we outline the phylogeny and biochemistry of RTKs with reference to myeloid ontogeny, classify the types of RTK mutation seen in myeloid malignancies, and discuss the prognostic and potential therapeutic significance of these acquired genetic changes. Of the many mechanisms for signal transduction across the cell membrane, the activation of cell surface receptors with inherent tyrosine kinase activity by growth factors is well understood. Tyrosine kinases are enzymes which catalyse the transfer of the γ-phosphate of ATP to tyrosine residues of protein substrates. There are at least 17 defined families of RTKs (Robertson et al, 2000). Each has a conserved structure with an extracellular ligand-binding domain, a transmembrane (TM) domain and an intracellular tyrosine kinase domain. RTK families differ primarily in their extracellular domains (Table I, Fig 1). Fig 1. Diagrammatic representation of receptor tyrosine kinase families (left) and key to domains (right) (after Robertson et al, 2000). EGF, epidermal growth factor; PDGF, platelet-derived growth factor; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; TRK, tropomyosin receptor kinase; AXL, anexelekto (Greek word for uncontrolled); LTK, leukocyte tyrosine kinase; ALK, anaplastic lymphoma kinase; TIE, tyrosine kinase with Ig and EGF homology domains; ROR, receptor tyrosine kinase-like orphan receptor; DDR, discoidin domain receptor; RET, rearranged during transformation; KLG, kinase-like gene; RYK, related to tyrosine kinase; MuSK, muscle-specific receptor tyrosine kinase. *The LTK gene was initially cloned on account of its homology with the intracellular domains of the insulin receptor. Subsequent studies have shown the locus to give rise to several differentially spliced isoforms with alternative extracellular domains (Toyoshima et al, 1993). The majority of RTK molecules are monomers. Exceptions include members of the closely related insulin receptor and ltk families, which exist as α2β2 heterotetramers, and members of the hgf family, which are αβ heterodimers (Fig 1). In all such cases, the receptor molecules are translated from a single precursor transcript and then undergo post-translational cleavage and modification in order to generate the final protein. RTK families differ primarily in their extracellular domains (Fig 1). Several structural motifs have been described (reviewed by Robertson et al, 2000). TM domains share a common alpha helical structure which not only anchors the molecule in the cell membrane, but also appears to play a critical role in receptor activation. The juxtamembrane region separates the TM domain from the cytoplasmic kinase domain. It is divergent between different RTK families, but highly conserved within them. The kinase domains are the most conserved components of the RTKs. Sequence alignments of a variety of receptor and non-receptor tyrosine kinases have defined 12 subdomains (I–XII) of high homology, containing at least nine invariant amino acids that are predicted to form the active site (Hanks et al, 1988). Crystallographic studies of the active and inactive conformations of the kinase domains of several RTKs have been made, and a conserved structure comprising eight alpha helices and eight beta strands has emerged (Hubbard et al, 1994, Johnson et al, 1996). All tyrosine kinases contain three large flexible protein domains, each bearing some of the invariant residues mentioned above. These are the activation loop (A-loop), whose conformation regulates kinase activity, the nucleotide-binding loop and the catalytic loop. The conformation of the A-loop (which comprises subdomains VII and VIII) is controlled by the phosphorylation of specific tyrosine residues within it. In the inactive state it blocks either the substrate or the ATP binding site of the enzyme. When phosphorylated, it is repositioned to contact residues in the C-terminal domain of the molecule (Mohammadi et al, 1996), thereby permitting enzyme activity. The nucleotide-binding loop contains hydrophobic residues responsible for binding the adenine moiety of ATP such that the γ-phosphate is in the correct position for catalysis. It is the least conserved part of the tyrosine kinase moiety and has been a major target in the development of receptor-specific tyrosine kinase inhibitors. The catalytic loop of protein kinases contains an invariant aspartate residue that serves as the catalytic base in the phosphotransfer reaction (Johnson et al, 1996). This is part of the highly conserved sequence His-Arg-Asp-Leu-Ala-Ala-Arg-Asn, present in the catalytic domains of several RTKs (McTigue et al, 1999). Many RTKs contain an insert of variable length and sequence in their kinase domains. This is known as the kinase insert domain (KID). Mutational analyses of several kinases have shown that the KID is not necessary for intrinsic kinase activity but that it contains tyrosine residues that are sites for autophosphorylation (Heidaran et al, 1991). The C-terminal tail lies downstream of the kinase domain and also contains target sites for autophosphorylation. Phosphorylation allows interaction with proteins containing src homology 2 (SH2) and phosphotyrosine-binding (PTB) domains that are critical for downstream signalling (Shewchuck et al, 2000). This process can be considered to occur in three sequential steps: ligand binding, signal transduction and kinase activation. Receptor activation is triggered by ligand binding, and is marked biochemically by tyrosine autophosphorylation at specific intracellular residues. The binding of a ligand to its RTK induces the dimerization of the monomeric receptors, the tetramerization of hepatocyte growth factor (HGF) family receptors, or a rearrangement of the tertiary and quaternary structures of heterotetrameric receptors, which in turn leads to receptor activation. The mechanism of receptor dimerization varies. Some ligands, e.g. platelet-derived growth factor (PDGF), are disulphide-linked dimers, while others, e.g. epidermal growth factor (EGF), are monomeric but have two receptor binding domains per molecule. Ligand binding can induce receptor homodimerization or heterodimerization. The mechanism by which ligand binding to and dimerization of RTKs drives tyrosine autophosphorylation is becoming clearer. While essential for receptor activation, ligand-induced receptor dimerization does not directly lead to increased kinase activity. Further conformational changes are required. Because of steric constraints, autophosphorylation probably represents the reciprocal transphosphorylation of the two receptor molecules within the ligand receptor complex (Schlessinger, 2000). Ligand binding is thought to lead to the apposition of the kinase domains of dimerized receptors by a mechanism critically dependent upon TM domain sequences. Only once this has occurred can transphosphorylation occur. It is known that the TM domains of several RTKs are functionally interchangeable and have conserved hydrophilic residues situated within the alpha helix such that they lie on the same face of the domain (Sternberg & Gullick, 1990; Ullrich & Schlessinger, 1990). It is thought that ligand binding leads to the coupled rotation of the paired RTKs within a receptor-ligand complex. Critically spaced hydrophilic residues located in the TM (and other) domains of each receptor are then able to form hydrogen bonds that hold them in a fixed orientation. This in turn brings the kinase domain of each receptor into contact with that of its partner, so permitting transphosphorylation (Bell et al, 2000). There are two hypotheses as to how receptor transphosphorylation might be initiated. One states that the kinase domains of unphosphorylated receptors have inherent low-level activity, with the highly mobile A-loop oscillating between an active and an inactive conformation. Ligand binding merely increases the local concentration of kinase domains (i.e. enzyme and substrate), thus increasing the likelihood of transphosphorylation. The other suggests that dimerization transiently stabilizes the A-loop in the active conformation and so substrate binding and phosphotransfer can occur. Once phosphorylation has occurred, the A-loop remains in the active conformation. There are no convincing data to distinguish between the two, but the target residues for phosphorylation are known in a variety of RTKs (Hubbard et al, 1998). Tyrosine phosphorylation of activated RTKs both promotes intrinsic kinase activity and generates sites of interaction for the various downstream phosphotyrosine-binding signalling proteins. All activated RTKs perform each of these functions to a greater or lesser extent. In keeping with this, there are two classes of tyrosine residue that are phosphorylated on receptor activation (Hubbard et al, 1998). Most RTKs contain up to three conserved residues in their A-loops which, when phosphorylated, stabilize an active conformation and permit catalysis. The other type of residue is less conserved and is located in non-catalytic positions. Phosphorylation here creates docking sites for downstream signalling molecules. There is a bewildering amount of data regarding intracellular signalling proteins. Classic genetics has predicted independent linear cascades of messenger activity downstream of each receptor, but molecular biology has found considerable overlap in the systems involved by both activating and inhibitory extracellular signals. The many signalling pathways can be considered to form a single homeostatic network capable of co-ordinating the many biological responses of a cell to its environment. There have been several recent and authoritative reviews in this area to which the reader is directed (Schlessinger, 1994, 2000; Pawson & Scott, 1997). During mouse development, the earliest intraembryonic cells with haematopoietic potential can be identified by the expression of vascular endothelial growth factor receptor 2 (VEGFR2)/flk1 protein (Shalaby et al, 1995). These primitive mesoderm cells ultimately give rise to definitive haematopoietic stem cells, which express c-kit. At an intermediate stage lies a c-kit+tie2+ cell, which is thought to represent a bipotent haematopoietic/endothelial precursor (Hamaguchi et al, 1999). Despite the general biological utility of RTK signalling and the interest in RTKs as potential therapeutic targets, there is a paucity of expression data for RTK proteins in normal and the RTKs whose expression has been at the protein in haematopoietic These studies have upon and in of in some cases, have been the it is that considerable of RTK expression within the in normal et al, 1999). of at the has been in normal cells and et al, and has been found in activated et al, 1997). expression has been a specific in normal myeloid in the mouse et al, 1995). The expression of various RTKs has increasing utility both as a and as an of in myeloid the Many studies have expression of various RTK proteins or in cell the most has the of cells directly from The majority of data has from the of acute myeloid which the in cells in these The of as a for is and protein expression is found in of in most et al, 1997). be found in an of et al, 1996), but it is also found in many acute thereby its utility et al, of other RTKs have been less and the of is protein has been found in of of et al, and protein in of of et al, There have been of et al, and et al, protein expression in Some studies have reaction to expression of RTK this has been found in of all et al, and in of et al, 1999). In this the that expression was with has shown in of of both chronic and acute et al, Some data has shown for protein in et al, 1997). In the studies to RTK expression has not been found to with of Only two have a in this et protein expression in and found it to with an In a protein and expression was found in of and a with was et al, 1999). In to their expression in myeloid there is data regarding specific in RTK genes in these Some studies of known to express or proteins have to a to the ligand in et al, 1996). This a activation of these molecules on account of acquired genetic by RTK molecules be predicted by the that many RTK genes have active which sequence expression of RTKs is in some myeloid there is as no for RTK per to a myeloid have been in RTKs of the receptor family and in fibroblast growth factor receptor The of most types of and the of proteins by specific and the of RTKs are thought to be the function of the proteins in most cases, genes are found to be with their In some these genetic changes are with defined There is data regarding and for involving other RTK genes have not been It is that these data in the of the gene with of a gene was in with the gene et al, was found to to three other genes in with in with with et and in with et al, 2000). In a gene has been described in with as a at the of of acute myeloid et al, 1997). The described to are in Of these the most is that with The majority of are described as either chronic myeloid with or as chronic with three are as chronic et al, & et al, 2000). of the for was increased in the or both (Table It that all with and genes have the same a amount of in the It for such to be as a specific with other with different and molecular genetic One of the most of this is the Only a single that was not at a molecular has been in a et al, 1996). The described with to other genes are a but was in in with and for all The either or with a in the described in for when at of acute myeloid in a it was with the of at in the tail region of have been in several and (Table The are in the at the mutation is with a The mutation the domain of the molecule has been found in This amino is conserved across all the protein found in the the same genetic et al, 1988). of has been in both and et al, 1990; et al, 1997). There is a regarding its prognostic The of the activation loop mutation in with has been for some (Table 1999). The with which represents a of some of which are is The mutation can be in from when studies are with or the of is with the mutation to involving and other domains of have been in (Table but these have been or by Of interest these is the kinase domain mutation seen in from et al, 1999). In suggests that this protein is not other RTK the high of expression of in the of might be in this The mutation has been found in some of (Table of these have been with cell and it is not the represents an of the cell have been with the or It is not the of is with or the of the recent has identified a of which all lead to of in the domain of present in et al, 1999). with was but the prognostic significance is in in has been to and studies of in this In the domain of the protein are found in cell from of and across all in the of (Table has been in and in In all of these are with In at least there is a to a et al, 1999). Mutations involving in the activation loop of the molecule are found in of These are to the changes c-kit. they are found in all and to have no bearing on et al, of the gene have been described most in with with of a gene et al, 1998). The same gene was described by two other et al, and et al, of have been described with or a related complex and a comprising a with lymphoma not and acute myeloid less acute (Table The has not been it has the for and for has been a in of the Some have shown and the of These represent a and be as a with other of or with of have been described with to the of a gene et al, et al, or which leads to of a gene et al, 1998). of these have been to of the with and they be as part of the same et al, They also have a with and with or lymphoma (Table have been described with acute with rearrangement of the include by et with two with a with and with and and chronic myeloid with cell with by et and probably an with The in at least two of these are to with but of a of is to they be as part of the same There is interest in the of the potential of the RTK proteins that have been in myeloid into the of in which they are and potential therapeutic for how a RTK potential is the of kinase (and activity. this as receptor dimerization and There are several at which RTKs be In tyrosine phosphorylation can be directed receptor dimerization be shown by studies can for the of cell to such analyses the gene to the studies involving can for the The is the most et al, The is such that the protein contains the TM and intracellular domains of but its extracellular domains are by the amino acids of the factor et al, 1996). This of the protein is known to contain a domain, the et al, 1997). The protein is phosphorylated and in and the gene haematopoietic cells to growth et al, 1996). Further analyses have shown the of the gene to be dependent upon a kinase domain and the to be dependent upon the sequences. It appears that the kinase domain of the protein is activated on account of dimerization by the domain. The protein has been shown to directly and the cytoplasmic factors and et al, messenger The expression of the gene the of an in leads to the development of and at a of its et al, 1999). be in the gene the of the et al, 1999). In the protein found in with all but the of the extracellular domains of et al, 1998). is a protein of which is capable of et al, 1997). The protein is phosphorylated and and it has been shown to haematopoietic cells to growth with phosphorylation of & 1999). Mutational studies that the domain of for is the for protein and but that from are essential for the to be & 1999). for protein dimerization and autophosphorylation to potential to that for the has been of the proteins involving and are less but both are proteins with domains necessary for an protein is by a of in some It is on account of motifs in the of the molecule et al, 1995). has been regarding this of The has been shown to induce growth in haematopoietic cells et al, 1998). These are the of the proteins with myeloid Most studies have the at in the mouse et able to autophosphorylation of and in proteins are not dimerized in the of ligand et al, some is for a form of receptor of an as cytoplasmic interaction specific to this et al, 1999). appears to target a different of substrate proteins to and cells this turn the tyrosine protein et al, 1996). The appears to target the the protein et al, 2000). and its mouse have both been shown to growth in haematopoietic cells et al, et al, 2000). bearing the mouse gene have also been shown to acute et al, 1996). less is regarding these proteins at The mouse of the domain is known to be phosphorylated and dimerized et al, 1996). In have shown that it can growth and induce acute when such cells are into The kinase domain is in that it is not phosphorylated in the of an protein. The significance of this is et al, 1999). These a of the domain of the protein and with a in Several molecular but in to the protein has been shown to be phosphorylated and dimerized et al, 1998). Some lead to the of which is essential for the phosphorylation of the protein. these are also studies have that can lead to growth and activation of et al, 2000). It is not known all are functionally in with the all are phosphorylated and induce growth in haematopoietic it is not the of kinase activity or the of is to of proteins. The of these is the protein which from a of the factor gene into of the gene in of et al, 1998). The protein contains the domains of to the and intracellular domains of reciprocal are in some et al, the is The protein is phosphorylated and and it induces growth of haematopoietic from the gene is for in with the a has emerged which receptor by a by the et al, 2000). The protein from the of the gene into of et al, 2000). The protein gene a protein identified by that is with the It domains, e.g. which play a role in The protein contains the amino of to the and intracellular domains of and its kinase domain is phosphorylated et al, 2000). Despite the by the protein of the protein does not with at stage in the cell et al, 2000). for kinase activity has been upon protein by domains in the sequences. The described protein from the of into of et al, 1999). The protein has to the domain of the function of is not and no data are the domains of a mechanism for receptor dimerization interaction of domains of the has emerged of active RTK molecules whose are their normal and which have acquired intracellular In some cases, normal RTK inhibitory mechanisms such as the tyrosine are et al, 1996). to these proteins have increasing recent can be to target RTK molecules and RTK gene as have the stage of are to or molecules to specific target are in order to their in They are to to and the by to thereby their In activity and so target are general therapeutic utility can be by them with molecules with specific activity which are able to target & 1998). and are in by and and for in have been have shown potential as in cell the gene & and et al, but the general of the has to be the of of at least some RTK molecules in and the of in the of some with it is that this has not been The only of directed RTK molecules has from the of a in et al, appears to be activated and in of expression thereby the of cells them by an In its with in has to an to molecule of both receptor and non-receptor tyrosine kinases have been known for some The a of the family, was for its to by various tyrosine kinase et al, 1991). In it was found to phosphorylation by several kinases that by related was found to have and of cells et al, 1996). There are several tyrosine kinase some of which are The known is the which have a role in the of et al, The molecule kinase activity by substrate to the nucleotide-binding site of the kinase domain et al, 1996). It has also been shown to the activity of and et al, as well as and the protein et al, 1997). in can be by of et al, 1999). It is that have a role as an in tyrosine kinase with activity and have been as in the of & 2000). they have not been in with in or of these is a tyrosine kinase that is highly specific for It has been as an in et al, 1999). The of this molecule in cells proteins has to be is a related molecule to and has been known for some as a of RTKs of the recent in has shown its to et al, Some RTKs to protein targets, and so downstream signalling pathways et al, 2000). There are that to target these they is a of a family of proteins that by a variety of receptors RTKs. It and active the post-translational of a to its et al, this process et al, et al, 2000). One such has shown in an in mouse of et al, but there is no data that it has in has been shown to activity in with utility remains to be defined et al, kinases form a of enzymes that some RTK at the cell surface (Schlessinger, 2000). of this of proteins are e.g. and They have to undergo but they are known to cells to et al, 2000). for specific in and expression of receptor tyrosine kinase genes in both acute and chronic has increased recent It is that the of involved genes The of defined of chronic in with specific genetic suggests in such cases, RTK represent a in the acute RTK occur during RTK proteins are potential for inhibitory The development of specific that target RTK ultimately lead to the development of to the of RTK expression of

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